ALBERT

Description: Introduction. Elderly patients with chronic lymphocytic leukemia (CLL) and younger patients with comorbidities are often treated with chlorambucil (Chl), despite the relatively low response rates. The addition of anti-CD20 monoclonal antibodies to Chl substantially increases the response rates, without negatively affecting tolerability. Overall response rates (ORR) between 66% to 84% have been reported with these combinations, with complete responses (CR)ranging from 8% to 26%. Methods. We conducted a retrospective analysis on the use of the Chl-rituximab (R) combination as frontline treatment for elderly (≥65 years) and/or unfit (CIRS 〉6) CLL patients treated at 15 different Italian hematologic centers. The main aim of the study was to further establish the safety and efficacy of the Chl-R protocol and investigate whether certain CLL patients for whom this protocol could be particularly effective could be identified. To this end, we performed a subgroup analysis stratifying patients according to FISH and IGHV results: high risk group (HR) included patients with 17p deletion, intermediate risk group (IR) patients with 11q deletion and/or unmutated IGHV, low risk group (LR) patients without 11q or 17p deletion and/or unmutated IGHV. Results. One hundred and two patients who underwent treatment between 2009 and 2011 were enrolled in the study. Patients' clinical and biologic characteristics are summarized in Table 1. Three patients discontinued treatment earlier than planned: 1 for an episode of autoimmune hemolytic anemia (AIHA) that developed after the 2nd cycle of Chl and before starting R treatment and 2 patients for disease progression after the 3rd and 5th cycle of Chl-R, respectively. The median number of Chl and R cycles administered in the 102 patients was 8 (range 2-12) and 6 (range 1-9), respectively. The planned treatment schedule was different among centers: the two main schedules used were Chl administered at 1 mg/kg for each cycle every 28 days, given at a fixed daily dose of 10 mg starting from day 1 and repeated for 8 cycles, and Chl administered at 8 mg/m2/day for seven days of each of eight 28-day-cycles. R was added to Chl from the 3rd cycle onwards and was administered on day 1 of each cycle at a dose of 375 mg/m2 during the first administration and 500 mg/m2 for the subsequent 5 cycles. On an intention to treat basis, the ORR was 87.1%. Thirty-two patients (31.7%) obtained a CR and 56 patients (55.4%) obtained a partial response (PR). Nostatistically significant differences were noted in terms of ORR for age above or below 70 years, fitness status, ECOG, bulky disease, cytogenetic risk abnormalities, IGHV mutational status, ZAP-70 or CD38 expression.Median progression-free survival (PFS) and time to retreatment (TTR) were reached at 43.7 and 72.3 months, respectively. Median overall survival (OS) was not reached; 86.1% and 81.2% of patients were alive at 48 and 60 months, respectively. The most frequent serious adverse event was grade 3-4 neutropenia, occurring in 13.7% of patients. Grade 3-4 extra-hematologic side effects were uncommon (9.8%). Subgroup analysis of the LR and IR patients (no HR patients were enrolled) showed that LR patients had a significantly better PFS than IR patients (65.8 months vs 35.2 months, p=0.001; Fig. 1),with 54.9% of patients remaining free from progression 60 months after treatment. Conclusions. Treatment of elderly and/or unfit CLL patients with the Chl-R regimen is associated with low toxicity, a high ORR and durable PFS. Particularly good results are achieved in CLL patients with a mutated IGHV profile and not carrying both 17p and 11q deletion, suggesting that in this low-risk subset of unfit patients Chl-R could represent the optimal therapeutic option, in consideration of safety, efficacy and costs. Disclosures D'Arena: Janssen-Cilag: Honoraria. Coscia:Gilead: Honoraria; ROCHE: Honoraria, Other: Advisory board; Janssen: Honoraria; Mundipharma: Honoraria; Karyopharm: Research Funding. Molica:Jansen: Membership on an entity's Board of Directors or advisory committees; Roche Italy: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Speakers Bureau. Efremov:Gilead: Honoraria.

Description: Introduction. Patients with CLL and FISH positive for trisomy 12 (+12) have unique clinical and biological features. We, therefore, performed an analysis of the association between demographic, clinical, laboratoristic and biological features and outcomes in treatment-naive patients with +12 CLL. Methods. This study included 312 treatment-naive patients with +12 CLL from 9 centers. These patients, diagnosed between January 2000 and July 2016, were compared to a control group of 580 treatment-naive patients with FISH negative CLL, matched by age and gender and followed in the same centers. An additional cohort of 250 patients with +12 CLL followed at a single US institution was used as external validation. Results. Patients' baseline characteristics are shown in Table 1. As compared to patients with negative FISH, patients with +12 had a significant higher prevalence of elevated LDH (p

Description: 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

Description: Introduction Elotuzumab (Elo), an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), received marketing approval in Italy for relapsed or refractory multiple myeloma (RRMM), in combination with lenalidomide (R) and dexamethasone (d) (EloRd) in April 2017. Here we report preliminary data of an Italian real-life experience on EloRd as salvage therapy for RRMM patients treated outside of controlled clinical trials. The primary objectives of this study were to assess the toxicity profile and the efficacy of EloRd administered as salvage therapy in a real-world setting. Methods Retrospective data collection received approval from local ethic committee. The cohort included 180 RRMM patients from 28 Italian centers who received at least one cycle of EloRd as salvage treatment between April 2017 and June 2018. Patients were treated with EloRD according to marketing approval as follows: Elo 10 mg/kg i.v. on days 1, 8, 15, and 22 during the first two cycles and then on days 1 and 15 of each following cycle, R 25 mg on days 1 to 21 of each cycle and d at a dose of 40 mg during the week without Elo, and 36 mg on the day of Elo administration. Responsive patients had to reach at least a partial remission (PR). Results Baseline characteristics are shown in Table 1. Median age of the 180 patients was 72 years (range 48-89 years); 53.9% were males (Table 1). The median number of previous therapy regimens was 1 (range 1-7); 69 patients (38.3%) received a previous autologous stem cell transplantation (ASCT). One hundred and ten patients (61.1%) showed a symptomatic relapse, 36 (20%) a biochemical relapse, and 34 cases (18.9%) were refractory to the last therapy, including bortezomib in 12.8% of patients. Forty-four patients (24.4%) had creatinine clearance ≤60 mL/min. Among the 138 cases evaluable for International Scoring System (ISS), 54 (39.1%) had stage I, 56 (40.6%) stage II, and 28 (20.3%) stage III. At last data collection (June 2018), 164 cases were evaluable for response. The median number of courses administered so far was 5 (range 1-18). The overall response rate (ORR) was 78%, with 9 complete remissions (CRs) (5.5%) and 49 very good partial remissions (VGPRs) (35.4%). A significant higher ORR was observed in patients who had received only 1 previous line of therapy than those who had received 〉1 line (64% vs 37.5%; p=0.004). Age (

Description: Background The role of single vs double autologous stem cell transplantation (ASCT) in patients with newly diagnosed (ND) multiple myeloma (MM) needs to be prospectively investigated in the novel agent era. Methods The phase III EMN02/HO95 study was designed to compare (first randomization, R1) (stratification according to ISS stage) standard-dose intensification therapy with bortezomib-melphalan-prednisone (VMP) vs high-dose intensification therapy with melphalan at 200 mg/m2 (HDM) followed by ASCT after 3-4 cycles of bortezomib-cyclophosphamide-dexamethasone as induction therapy. A second randomization to consolidation therapy vs no consolidation was performed after intensification therapy, to be followed by lenalidomide maintenance until progression or toxicity in both arms. A primary study endpoint was progression-free survival (PFS) from R1. In centers with a policy of double ASCT, patients were randomized in a 1:1:1 ratio to either VMP or single ASCT (ASCT-1) or two sequential courses (administered 2 to 3 months apart) of HDM and double ASCT (ASCT-2) in order to prospectively compare ASCT-1 with ASCT-2, which was an additional study objective. Results From February 2011 to April 2014, 1510 pts aged ≤65 years with symptomatic NDMM were registered and 1192 of these were eligible for R1. According to the design of the study, 614 eligible patients who received the diagnosis of MM in centers with a double intensification policy were randomly assigned to either VMP (n=199) or ASCT-1 (n=208) or ASCT-2 (n=207). Patients randomized to ASCT-1 or ASCT-2 were included in the current pre-specified analysis. Median age was 59 years for patients in the ASCT-1 group and 57 years for those in the ASCT-2 group. The frequency of ISS stage III was 18% and 19%, while revised ISS stage III was 9% and 11%, respectively. Cytogenetic abnormalities were detected by FISH analysis of CD138+ plasma cells. A high-risk (HR) cytogenetic profile, defined by t(4;14) and/or del(17p) and/or t(14;16) (HR cyto-3), was observed in 26% of evaluable patients who were randomized to ASCT-1 and in 21% of those randomly assigned to ASCT-2. If amp(1q) and/or del(1p) were added for the definition of high-risk disease, a HR cytogenetic profile that included at least 1 of the 5 above mentioned chromosomal abnormalities (HR cyto-5) was reported in 55% of evaluable patients in the ASCT-1 group and in 54% of those in the ASCT-2 group. Median follow-up from R1 was 27 (IQR: 20-35) months. On an intention-to-treat basis, the median PFS was 45 months in the ASCT-1 arm and was not yet reached for patients in the ASCT-2 arm; 3-year estimates of PFS were 60% and 73%, respectively (HR=0.66; 95% CI=0.45-0.96; P=0.030). PFS benefit with ASCT-2 was retained across predefined subgroups, including patients with β2-microglobulin 〉3.5 mg/L (HR=0.59; CI=0.34-0.99; P=0.005), bone marrow plasma cells 〉60% (HR=0.41; CI=0.22-0.77; P=0.006), LDH values above the upper limits (HR=0.52; CI=0.28-095; P=0.034), revised ISS stage II (HR=0.50; CI=0.31-0.80; p=0.004), HR cyto-3 (HR=0.49; CI=0.24-1.02; P=0.057) and HR cyto-5 (HR=0.57; CI=0.35-0.93; P=0.024). In a multivariate Cox regression analysis stratified by ISS stage, randomization to ASCT-2 (HR=0.62; CI=0.40-0.95; P=0.027) and HR cyto-5 (HR=2.63; CI=1.63-4.16; P

Description: Abstract 200 Background: In a multicenter phase 3 randomized trial, VMPT-VT was superior to VMP for response rates, progression-free survival and time to next treatment (Palumbo A, et al. J Clin Oncol 2010). Here we report an updated analysis on survival after 4 years of follow-up. Methods: Patients (N=511) were randomly assigned to receive nine 6-week cycles of VMPT-VT (induction: bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, thalidomide 50 mg d 1–42; maintenance: bortezomib 1.3 mg/m2 every 14 days and thalidomide 50 mg/day up to 2 years) or VMP alone. After the inclusion of 139 patients, the protocol was amended: both VMPT-VT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 d 1,8,15,22, all cycles). Results: After a median follow-up of 47.2 months, median OS was not reached in the VMPT-VT arm and was 58.2 months in the VMP arm; 5-year OS rates were 59.3% and 45.9%, respectively (HR 0.74, p=0.04), with 26% reduced risk of death for patients receiving VMPT-VT (Figure-panel A). This benefit was more evident in patients younger than 75 years (5-year rates 67.8% for VMPT-VT vs 49.9% for VMP, HR 0.63, p=0.01, Figure-panel B) and in patients in complete response (CR) after induction (5-year rates 81.4% for VMPT-VT vs 48.2% for VMP, HR 0.38, p=0.006, Figure-panel C) while no significant differences were evident in patients with standard- or high-risk features detected by FISH (HR 0.99, p=0.99). A 1-year landmark analysis for patients completing induction was performed: the 4-year OS was 64.6% in the VMPT-VT group and 49.7% in the VMP group, with 33% reduced the risk of death for patients receiving VT maintenance (HR 0.67, p=0.02). Forty-nine percent of VMPT-VT and 70% of VMP patients relapsed and received subsequent salvage therapies; there was no difference in survival from relapse in the two groups (2-year OS rates 40.7% vs 50.2%,HR 1.11, p=0.54). The median duration of VT maintenance was 23.8 months. During VT maintenance 7% of patients experienced grade 3–4 peripheral neuropathy, 5% grade 3–4 hematological toxicity, 3% grade 3–4 infection and 12% discontinued due to adverse events. Second primary malignancies were reported in 7/254 patients in the VMPT-VT group and 7/257 patients in the VMP group. These corresponded to incidence rates of 0.9 and 1.05 per 100 patient-years, respectively, and were consistent with background incidence rates in the general population (aged 65–74 years 1.9, aged ≥ 75 years 2.3, SEER database). Conclusions: VMPT-VT significantly prolonged OS compared with VMP, especially in patients younger than 75 years and in patients achieving CR after induction. In patients 67–75 years of age, VMPT-VT reduced the risk of death by 37% and it should be considered a new standard of care. Disclosures: Palumbo: Celgene: Advisory Board, Advisory Board Other, Consultancy, Honoraria; Janssen: Advisory Board Other, Consultancy, Honoraria. Bringhen:Janssen: Honoraria; Celgene: Honoraria. Gentilini:Janssen: Honoraria; Celgene: Honoraria. Patriarca:Janssen: Honoraria. Guglielmelli:Janssen: Honoraria; Celgene: Honoraria. Musto:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Petrucci:Janssen: Honoraria; Celgene: Honoraria. Boccadoro:Janssen: Consultancy, Research Funding, Scientific Advisory Board Other; Celgene: Consultancy, Research Funding, Scientific Advisory Board, Scientific Advisory Board Other.

Description: Introduction. Observational studies from patients treated outside controlled clinical trials offer real life information and are relevant to understand whether data derived from prospective trials are reproducible in the clinical practice. A retrospective observational study was carried out by the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) group in order to evaluate the clinical characteristics and outcome of patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib in Italy within a Named Patient Program (NPP). The NPP was intended to offer free and early drug access to CLL patients until ibrutinib became available on the Italian market. Methods. Patients included in the NPP program had refractory or relapsed (R/R) disease with progression within 24 months after prior chemo-immunotherapy, and/or 17p deletion/TP53 mutations. Patients were also required to have an ECOG performance status ≤2; serum creatinine ≤2 times, liver enzymes ≤3 times and total bilirubin ≤1.5 times the upper limit of normal. Key exclusion criteria were: the need of a concomitant treatment with a strong CYP3A inhibitor or warfarin, an allogeneic stem cell transplantation within the past 6 months or an ongoing active infection. All patients included in the program received ibrutinib orally as a single agent at the standard dose of 420 mg daily. Clinical data of 110 patients included in the NPP program between January 2014 and November 2014 have so far been collected and analyzed using the Research Electronic Data Capture (REDCap) system. Patients were managed at 20 Italian centers and received at least one dose of ibrutinib. Clinical data were reported by the treating physicians. Results. The median age of patients was 69.9 years (range 49.8-83.3); 53% were in Rai stage III-IV, 32% in stage II and 15% in stage 0-I. Sixty-two percent of patients had relapsed disease, 38% were refractory to prior treatment. The presence of a 17p deletion and/or TP53 mutations was recorded in 51 R/R patients. Eighty-six percent of patients had an unmutated IGHV gene profile. The median number of prior treatments was 3 and included allogeneic stem cell transplantation in 4 cases. Two or more comorbidities were reported in 57 patients (52%) and included atrial fibrillation (AF) in 10 (9.1%) and hypertension in 40 (36.4%). After a median follow-up of 12.1 months (range, 1.6-24.6), 87 patients (79%) were still on ibrutinib. A response to ibrutinib was reported in 98/110 patients (89.1%). The best recorded response was a CR/CRi in 19 patients (17.3%), while a PR was reported in 79 patients (72%; PR-L 21.1%). Similar response rates were observed in patients with unmutated IGHV genes (91.9%) and in those with 17p deletion/TP53 mutations (90.3%). At 12 months, the progression-free survival (PFS) and overall survival (OS) were 92.9% (95%CI: 87.9-98.2) and 95.2% (95%CI: 91.1-99.4), respectively. PFS at 12 months of patients who achieved a response was 96.3%, 98.9% in unmutated IGHV patients, 90.7% in those with 17p deletion/TP53 mutations. Five patients (4.5%) died during the NPP program (1 patient each for sepsis, heart failure, ileus perforation, cancer, unknown cause). Adverse events (AE) were recorded in 75 patients (68.2%); in 47 (42.7%) they were grade ≥3. Any grade AEs recorded in ≥5% of patients were: infections (35%; grade ≥3, 22%), granulocytopenia (18.8%; grade ≥3, 17.2%), bleeding (15.5%; grade ≥3, 2.7%), fever of unknown origin or febrile neutropenia (12%; grade ≥3, 5.4%), AF (10.9%; grade ≥3, 4.5%), diarrhoea (8.3; grade ≥3, 2%), hypertension (7.2%; grade ≥3, 5.4%). A new event of AF occurred in 1/10 patients with a prior history of AF. Warfarin was required in 1 patient with AF and this was the reason for ibrutinib discontinuation. Conclusions. The results of the first interim analysis of this retrospective, real life study confirms that ibrutinib, as a single agent, is an effective treatment for patients with poor-prognosis CLL. Our data also suggest that ibrutinib given to unselected patients, in a compassionate-use program, shows a clinical activity and a safety profile comparable to those reported in prospective trials. Data collection is ongoing in order to complete the analysis of this large NPP cohort in Italy. Disclosures Marasca: Roche: Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria. Coscia:Karyopharm: Research Funding; ROCHE: Honoraria, Other: Advisory board; Janssen: Honoraria; Gilead: Honoraria; Mundipharma: Honoraria. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees. Molica:Jansen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche Italy: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Speakers Bureau. Orlandi:Ariad: Honoraria; BMS: Honoraria; Novartis: Honoraria. Ghia:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Adaptive Biotechnology: Consultancy; Roche: Honoraria, Research Funding. Foà:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy; Genentech: Consultancy; Pfizer: Speakers Bureau; Ariad: Speakers Bureau.

Description: Abstract 1851 Background: Bendamustine, an agent sharing properties of alkylators and purine analogous, showed a strong efficacy and safe toxicity profile in relapsed multiple myeloma (MM) patients (pts), with a maximally tolerated dose (MTD) ranging from 100 mg/m2/die day 1 and 2 as single agent to 60 mg/m2/die in association with thalidomide. In a pooled analysis of two large phase 3 trials Lenalidomide, an analogous of thalidomide with strong activities in MM, significantly improved overall response rate and progression-free survival. Since the role of Lenalidomide in the treatment of naïve and relapsed/refractory pts has been well established, the current research is focused on the combination of Lenalidomide with chemotherapy to further improve patient outcome. Methods: This multicenter phase I/II trial was designed to investigate the combination of Bendamustine, Lenalidomide, and Dexamethasone (BdL) in repeating 4-week cycles as treatment for relapsed MM. Pts over 18 years with measurable stage II or III MM who relapsed after 1 to 3 previous lines of therapy, including bone marrow transplantation were considered eligible. Prior Lenalidomide and Bortezomib were allowed. The phase I study was conducted using a 3+3 cohort design beginning at a dose level 0 of intravenous Bendamustine 40 mg/m2/die days 1 and 2, oral Lenalidomide 10 mg/die days 1–21 and oral Dexamethasone 40 mg/die days 1, 8, 15, and 22 (28-day cycle). The dose of Bendamustine and Lenalidomide (from 0 to 5) were increased from one cohort to the next, in a 3+3 dose escalation scheme to reach the MTD (Table 1). The MTD of Bendamustine and Lenalidomide were evaluated during the first treatment course (cycle 1). Enrollment at each subsequent dose level was permitted only if the first 3 patients at the previous level received 1 cycle with an acceptable dose-limiting toxicity (DLT). DLTs were defined as any adverse event (AE) possibly related to the study drug ≥grade 3 CTC. If 1 of the 3 subjects experienced DLT during the first cycle, 3 more subjects were to be recruited and treated at the same dose level of Bendamustine and Lenalidomide. Treatment was given until plateau of best response according to the International Myeloma Working Group uniform response criteria for a maximum of 6 cycles. Results: Herein, we present the results from phase I of the study which established MTD. Fifteen pts with a median age of 69 years (range 49 to 88) were enrolled between October 2011 and February 2012. The number of prior therapies was at maximum 3 as per protocol: Lenalidomide (27% of pts), thalidomide (33% of pts), Bortezomib (67% of pts) and 13% of the pts had a prior autologous stem cell transplant. Because 3 DTL were observed in Phase I, the MTD was set at 40 mg/m2/die for Bendamustine and 10 mg/die for Lenalidomide. DLTs at dose level 1 included: 1 grade 4 cutaneous rash; at dose level 2: 1 grade 4 thrombocytopenia and 1 grade 3 bronchopneumonia with renal dysfunction (Table 2). Among the 15 patients with evaluable data, the grade 3 or 4 AEs observed in ≥10% of patients included neutropenia (20%), thrombocytopenia (13%) and anemia (20%). Two patients died of treatment-related complications: 1 for hematological toxicity and CNS hemorrhage, and 1 for cardiac ischemia. Fifteen patients received at least 2 cycles and were included in the response assessment. The overall response rate was 40% with 1 case achieving complete response and 1 a very good partial response. Until now 7 pts entered the phase II part of the trial. Conclusions: In pretreated patients with relapsed MM, MTD was determined to be Bendamustine 40 mg/m2/die on days 1 and 2, and Lenalidomide 10 mg/m2/die on days 1–21, plus Dexametasone 40 mg/die on days 1, 8, 15, and 22. This BdL schedule was relatively tolerated and showed promising efficacy. Based on the mainly myelosuppressive properties, concomitant treatment with growth factors are recommended for all patients. The toxicity profile of BdL scheme resulted in an acceptable treatment-related toxicity and mortality and induced a good quality responses in a pretreated population of MM pts. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2971 Introduction: Bendamustine is a bifunctional alkylating agent approved for the treatment of several lymphoproliferative disorders. Studies have evidenced its efficacy in multiple myeloma (MM), but data so far available in this setting are scarce. We performed a retrospective analysis of Italian patients with relapsed/refractory MM, who had received bendamustine as salvage therapy within a national compassionate use program. Patients and methods: Seventy-eight patients (42 males, 36 females) were collected in 19 hematological centers. Mean age was 64.2 years (range 38–84). ISS was equally distributed, with about one third of patents being represented in single stages. Twenty-three of 43 analyzed patients had cytogenetic abnormalities, the most frequent being del13q (14 patients); t(4;14) and t(11;14) were observed in 4 and 2 patients, respectively, while t(6;14), del17p or complex karyotype occurred in single patients. The median number of prior lines of therapy was 4 (range 1–10). Ninety-seven percent of patients had previously received bortezomib, 94% IMIDs, 85% melphalan, 74% cyclophosphamide, 45% anthracyclines, 26% other drugs, 33% radiotherapy. Sixty percent of patients had undergone autologous and 4% allogeneic stem cell transplantation. The last treatment before bendamustine was a bortezomib-based regimen in 31%, an IMIDs-based regimen in 42%, a combined bortezomib/IMIDs-based regimen in 9%, while 18% of patients had received other therapies. Seventy-three percent of patients were resistant to last therapy received, while 27% had relapsed. Median duration of response to last treatment received before bendamustine was 9 months (range 2–46). Median Hb value was 10.1 g/dl (range 7.6–14.9), WBC count 2.700/μl (range 550–15.200), PLT count 130.000/μl (range 6.000–410.000). Serum creatinine, calcium, beta2-microglobulin and LDH levels were increased in 12 (15%), 4 (5%), and 44 (56%) patients, respectively, while albumin levels were decreased in 27 patients (35%). The median percentage of marrow plasma cells (as evaluated in 57 cases) was 60% (range 1–100). Seventy-six percent of patients had osteolytic bone involvement and 78% extramedullary localizations, with 13% showing secondary plasma cell leukemia and 7% documented amyloidosis or proteinuria. Finally, 45% of patients presented with at least one severe comorbidity, mainly cardio-vascular, liver or pulmonary dysfunction, and diabetes. Results: A total of 236 cycles was administered (median 3, range 1–9). In 47% of patients bendamustine was variously associated to bortezomib (23%), or IMIDs (21%), or to a combination of both (3%). In 80% of patients receiving bendamustine +/− steroids, a median dose of 90 mg/sqm for two consecutive days every 28 days was employed; the median dose was 80 mg/sqm when bendamustine was combined with bortezomib, 60 mg/sqm with IMIDs (total range: 40–140 mg/sqm). The remaining patients received single, monthly doses ranging from 60 to 150 mg/sqm. According to IMWG uniform response criteria, 21 out of 73 evaluable patients achieved a response after a median time of 3 months. In particular, there were 16 PR, 1 VGPR, 1 sCR, and 3 CR; overall response rate (ORR) was, therefore, 29%. Response rate was 10% (4/39) in bendamustine single agent +/− steroids, 38% (5/13) in bendamustine + bortezomib and 62% (10/16) in bendamustine + IMIDs subgroups, respectively. Responders had received a lower number of previous treatments than non responders (median 3 vs 4). Response rate was higher in relapsed (12/21, 57%) than in resistant patients (10/57, 17%). The time to best response ranged from 1 to 8 months. After a median follow-up of 8 months, median PFS duration was 6 months, with 13 out of 21 responding patients not yet progressed. Median OS of the entire cohort was 6.2 months (7 months in responders and 4 months in non responders, range 0–27). Grade 3–4 hematological and non-hematological toxicities occurred in 56% and 15% of patients, respectively, causing three interruptions of the treatment. Conclusions: Though with the clear limits due to the high heterogeneity of treatments applied and of population analyzed, our data indicate that bendamustine may be a therapeutic option in heavily pretreated MM, suggesting a possible non cross-resistance with other agents. Its earlier use with appropriate doses and combinations might further improve the results obtained in this study. Disclosures: Musto: Mundipharma: Honoraria. Off Label Use: Bendamustine in relapsed/refractory myeloma. Fragasso:Mundipharma: Honoraria. Baldini:Mundipharma: Honoraria. Storti:Mundipharma: Honoraria.

Description: Introduction Heavy light chain (HLC) assay is a recently developed method that separately quantifies the k and L-bounded amounts of a given intact immunoglobulin (Ig). It allows an accurate quantification of both the involved/uninvolved Ig and permits to quantify even small monoclonal protein. Free light chain (FLC) and HLC can provide prognostic information for multiple myeloma patients. We evaluated the role of HLC and FLC tests in the assessment and evolution of the disease in newly diagnosed multiple myeloma (MM) patients. Methods From February 2011 to April 2014, 1510 patients aged ≤65 years with symptomatic newly diagnosed MM were enrolled in the EMN02/HO95 study. Details about treatments and preliminary results of the main study were previously reported (Cavo M et al, abs8000, J Clin Oncol 34, 2016). In this analysis, we focused on patients enrolled in Italy (N=718). Serum samples from each enrolled patient were collected at diagnosis, before starting maintenance, and thereafter every 6 months. Samples from 665 patients at diagnosis and 156 at pre-maintenance were analyzed. Involved HLC ratio (iHLCR) was calculated with the involved Ig (either G or A) as numerator. Involved FLC ratio (iFLCR) was calculated as K/L or L/K with the monoclonal chain as numerator. FLC ratio (FLCR) and HLC ratio (HLCR) were calculated as K/L. The analyses were performed using Spearman correlation. Results Median follow-up was 32 months. At baseline the type of paraprotein was IgG in 428 (298 IgG-k, 130 IgG-L), IgΑ in 123 (77 IgΑ-k, 46 IgΑ-L) or light chain in 104 patients (k 73, L 31); 10 patients were IgD or IgM. International Staging System (ISS) stages were well distributed in all the isotypes. The median involved HLC values were IgG-K 28.97, IgG-L 30.6, IgA-K 41.7, IgA-L 35.7 g/L, light chain K 2719.58 mg/L, and light chain L 3369.75 mg/L. HLC IgG was significantly correlated with B2-microglobulin (r=0.31), extensive bone marrow infiltration 〉60% (r=0.31) and hemoglobin (r=-0.39). HLC IgA was not correlated with any disease parameter. In light chain MM, iFLC was correlated to B2-microglobulin (r=0.41), creatinine (r=0.39), extensive bone marrow infiltration 〉60% (r=0.39) and hemoglobin (r=-0.36). The increase of iFLCR (≥ median value) was significantly associated with IgG, ISS III, anemia, extensive bone marrow infiltration and higher creatinine (p third quartile) was significantly associated with inferior TTP (median 43.4 versus NR, HR 1.75 95% CI 1.22-2.53, p 0.003). The increase of iHLCR (≥ median value) was significantly associated with ISS III, anemia, and extensive bone marrow infiltration (p