ALBERT

Description: Complete response (CR) is an important objective of autologous stem-cell transplantation (ASCT) in multiple myeloma (MM). In comparison with conventional induction treatments, newer combinations of novel agents may effect increased rates of CR and near CR (nCR), a benefit potentially translating into even higher frequencies of CR/nCR after ASCT and improved clinical outcome. We designed a phase III study to detect an increase in CR+nCR rates from 10–15% with conventional Thalidomide-Dexamethasone (TD) to 20–30% with Velcade added to TD (VTD) in newly diagnosed MM. Both TD and VTD were given as three 21-day cycles in preparation for double ASCT. In the present analysis, CR+nCR rates by the two induction treatments were examined in relationship to baseline prognostic variables in 399 evaluable pts aged ≤65 years, of whom 199 randomized to VTD and 200 to TD. All analyses were intent to treat. In comparison with TD, VTD effected higher rates of CR+nCR (12% vs 33%, P

Description: Background. Allogeneic hemopoietic stem cell transplantation is the treatment of choice for high and intermediate risk acute myeloid leukemia (AML) and for higher risk myelodysplastic syndrome (MDS). Standards preparative regimens TBI-CY and BU-CY have been widely used and extra hematologic toxicity remains a concern. Even if the combination of intravenous formulation Busulphan-CY has shown lower toxicity and suggested favorable safety and efficacy profile new drugs associations are continuously explored. Recently the association Busulphan-Fludarabine has replaced the Bu-Cy regimen with the aim to further reduce toxicity. In our Institution we started to use this regimen as preparation for allogeneic transplantation in patients with AML and MDS in October 2008 using Busulphan in a single daily infusion with the primary objective of evaluating safety and efficacy. Methods. Since October 2008 to May 2014, 23 consecutive patients (19 males, 4 females) entered this study. Median age was 56 years (range 35-63). Thirteen patients presented with first remission AML, five with first or more advanced relapse or resistant disease and five with intermediate II or high risk MDS. Conditioning consisted of intravenous Busulphan (Busilvex® 9,6 -12,8 mg/kg) given once daily in a 4 hours infusion in association with Fludarabine 160 mg /m2 for 4 consecutive days. Fifteen patients received HSCs from HLA identical siblings, 1 from a family mismatched donor, 7 from matched unrelated donors. Source of stem cells was bone marrow in 13 patients, peripheral blood stem cells in 9 patients, and both in 1 patient. CSA + short MTX was used as GVHD prophylaxis and anti-Lymphocyte globulins (Thymoglobulin® or ATG Fresenius®) was added in case of unrelated donor transplants Toxicity was evaluated by WHO toxicity scale Common Terminology Criteria for Adverse Events (CTCAE) version 3. Acute Graft versus Host Disease was evaluated in patients with engraftment and graded according to the revised Glucksberg scale. Internal review board approved study. All patients gave written informed consent to procedure. Results. All patients regularly engrafted (mean time to neutrophils 〉500/microliter was 13 days (range 11-15). Seven patients experienced gastro-intestinal toxicity (1 grade III mucositis, 2 grade II mucositis, 4 grade I mucositis); 3 patients had grade II cystitis. Overall grade 〉II toxicity occurred in a single patient (4%). Acute grade IV gastro-intestinal- GvHD occurred in 1 patient, while 12 patients presented grade I skin GvHD. Cr. GVHD occurred in 4/18 evaluable patients (moderate in 1). CMV reactivation occurred in 15/23 patients (65%), no patient developed life-threatening bacterial or fungal infection. Eight out of 23 patients have died (35%) all but one by recurrent disease and 1 by grade IV acute GvHD. Fifteen patients are alive (65%), 14 in complete remission, with a median follow-up of 8 months (range 2-37 months). Conclusion. This single Centre report, even if with limited number of patients, underlines that the association of intravenous single dose infusion Busulphan plus Fludarabine is a safe and effective conditioning regimen in AML/MDS patients. Intravenous Busulphan administered once daily is convenient, well tolerated and effective. Further prospective studies are warranted. Disclosures No relevant conflicts of interest to declare.

Description: In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.

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: The initial analysis of the oral combination melphalan, prednisone, and thalidomide (MPT) in newly diagnosed patients with myeloma showed significantly higher response rate and longer progression-free survival (PFS) than did the standard melphalan and prednisone (MP) combination and suggested a survival advantage. In this updated analysis, efficacy and safety end points were updated. Patients were randomly assigned to receive oral MPT or MP alone. Updated analysis was by intention to treat and included PFS, overall survival (OS), and survival after progression. After a median follow-up of 38.1 months, the median PFS was 21.8 months for MPT and 14.5 months for MP (P = .004). The median OS was 45.0 months for MPT and 47.6 months for MP (P = .79). In different patient subgroups, MPT improved PFS irrespective of age, serum concentrations of β2-microglobulin, or high International Staging System. Thalidomide or bortezomib administration as salvage regimens significantly improved survival after progression in the MP group (P = .002) but not in the MPT group (P = .34). These data confirm activity of MPT for PFS but failed to show any survival advantage. New agents in the management of relapsed disease could explain this finding. The study is registered at www.clinicaltrials.gov as #NCT00232934.

Description: Introduction Lenalidomide (Len) and low-dose Dexamethasone (dex) (Rd) in continuous is a new standard of care for elderly newly-diagnosed multiple myeloma (NDMM) patients (pts), as established by FIRST trial (Facon et al, Blood 2018). Methods and results This is a retrospective, multicentric study conducted in Italy with the aim of evaluating efficacy and tolerability of Rd in a real-life population. Thirty-seven centers were involved and data of 429 pts are available. Pts were considered eligible for the study when completing at least 2 cycles of Rd regimen. Table 1 summarizes the characteristics of pts at time of MM diagnosis. Median age was 78 years (range 57-92), 36.6% had an ECOG PS≥2, creatinine clearance (ClCr) was ULN (P=0.01) and ClCr2 still impact on OS (p

Description: Background: Hodgkin Lymphoma (HL) is a neoplastic hematologic disease that requires treatment with standard chemo-radiotherapy and, in relapsed patients, intensification with hematopoietic s cell transplantation (HCT). Introduction: Insertion of a Peripheral Insertion Central Venous Catheter (PICC) instead of a Peripheral Venous Catheter (PVC) could simplify HL patients management and allow a safer therapy, according to their outpatient care. Methods: Since the 2007, a PICC team, consisting of an hematology physician and two dedicated nurses has carried out a prospective study to evaluate complication rate and usefulness of PICC device in the hematology clinical practice, particularly in HL patients. Inclusion criteria included all HL inpatient and outpatient who needed program of chemo-radiotherapy, support treatment and HSCT, regardless of white blood cells (WBC) and platelets (PLT) counts. All patients underwent a previous evaluation of arms vascular anatomy by ultrasonography. All implantation procedures were performed under ultrasound guide with radiographic control following insertion. Results: From March 2007 to January 2018, 228 attempts of PICC implantation were performed in 202 HD patients (104 male and 90 females). Median age was 35 years, range 16-85. Catheter insertion was successful in 220 cases (96.5 %) in 194 patients, whilst in 8 cases (3.5%) PICC insertion was not possible; 96 PICC were inserted in patients treated with a previous chemotherapy. Two hundred and seven PICC (94%) were used for chemo-radiotherapy courses, five (2.3%) for support treatment, 7 (3.2%) for autologous HSCT, 1 (0.5%) for allogenic HSCT. At the time of this analysis 7 out of 220 PICC (3.5%) are still in situ and in use, 180 (81.5%) were removed for end of therapy and 10 (4.5%) for accidental withdrawals. Only 23 PICC (10.5%) were removed because of catheter related complications: 2 (0.9%) for catheter rupture, 4 (1.8 %) for malfunctioning, 7 (3.2%) for occlusions, 4 (1.8%) for local infection, 6 (2.7%) for suspected PICC-related sepsis. Only 3 episode of confirmed PICC-related septicemia (1.4 %; 0.1/1000 days/PICC) were recorded and Staphylococcus was isolated. There were only 5 episodes (2.3% ; 0.14/1000 days/PICC) of symptomatic PICC-related thrombotic complications, without need of removal. Two cases (0.9%) of delayed abnormal dislocation were recorded, fixed with subsequent replacement with guide. PICC median life was 157 days (range 1-396) for a total of 34,764 days. The 365-day cumulative incidence of catheter removal for end of therapy (PICC life) was 95,5%±1.7%. No significant difference was found in patients underwent previous chemotherapy course (95.1±2.6 vs 95.8±2.1%, p=NS). Neither stage of disease WBC or PLT count had influenced on PICC life. Conclusions. These data encourage the use of PICC as standard of care in the management of HD patients because of easy insertion, safety of use, duration of life and low rate of complication. Disclosures Angelucci: Celgene: Honoraria, Other: Chair DMC; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Roche Italy: Other: Local (national) advisory board.

Description: Introduction: The phase 3 GIMEMA-MMY-3006 trial comparing bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (MM) provided the first demonstration of increased CR rate, the primary study endpoint, and prolonged PFS with VTD (Cavo M et al, Lancet 2010). However, updating trial results with longer follow-up than earlier reported is needed to assess the effects of treatment interventions on OS and to identify factors predicting for favorable long term outcomes. Aims: We performed a post-hoc analysis of that study to evaluate long term results and construct a prognostic index of survival. Methods: 474 patients were enrolled, 236 randomized to VTD and 238 to TD. Median follow-up for surviving patients was 124 months (IQR: 117-131). Analyses were performed on an intention-to-treat basis. Semi-parametric Cox regression analysis was used to construct the prognostic index. To assess the evolution of prognosis over time, conditional survival CS(t|s) estimate for PFS was calculated as the probability of surviving without progression a further 2 (t) years (yrs) after having already survived s yrs. Results: Estimates of PFS and OS at 10 yrs for the VTD arm were 34% (HR=0.62; 95% CI=0.50-0.77; p

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: Abstract 2811 Poster Board II-787 Introduction The recurrent translocation t(4;14)(p16;q32) occurs in less than 20% of patients with newly diagnosed Multiple Myeloma (MM) and is associated with a poor clinical outcome following either conventional or high-dose chemotherapy. Recently, it has been reported that patients carrying t(4;14) are prognostically heterogeneous and that the novel agents bortezomib and lenalidomide may overcome the poor prognosis related to this cytogenetic abnormality. In the present study, we analyzed the gene expression profile of patients who carried or not t(4;14) and were primarily treated with a bortezomib-based regimen. Patients and methods Two hundred thirty six patients with MM who received a combination of bortezomib-thalidomide-dexamethasone (VTD) as first-line therapy were evaluated for the presence at diagnosis of t(4;14). Of these, 41 patients (17.3%) were t(4;14) positive. On an intention-to-treat basis, the rate of CR and near CR (nCR) to VTD induction therapy among patients carrying t(4;14) was 41%, a value higher than the 29% observed among t(4;14) negative patients. In 218 patients for whom data on t(4;14), del(13q) and del(17p) were available, the differential gene expression of CD138+ enriched plasma cells was evaluated by means of expression microarray using the Affymetrix platform. The analysis was performed in t(4;14) negative patients and patients carrying t(4;14), either alone or combined with other abnormalities; t(4;14) negative patients included those with del(13q) alone and with any of these abnormalities. Results In 27 patients, t(4;14) was associated with either del(13q) (24 patients) or del(17p) (3 patients); the remaining 14 patients carried t(4;14) alone. The expression profiles of patients carrying either t(4;14) alone or t(4;14) combined with del(13q) significantly clustered apart when compared with those of cytogenetic negative patients. Similarly, the expression profiles of patients with del(13) alone clustered with those of cytogenetic negative patients. De-regulated expression of similar molecular pathways was demonstrated in patients carrying t(4;14) alone or combined with del(13q). Thus, the analysis of gene expression profiles according to response or no response to VTD was performed in two subgroups of patients, including those carrying t(4;14) alone or combined with del(13q) and those carrying either del(13q) alone or without cytogenetic abnormalities. By comparing the lists of genes differentially expressed (P '0.05) in patients who responded (e.g. those who achieved CR+nCR) and failed to respond (NR) to VTD according to the presence or absence of t(4;14), we found that the differential expression of 3719 genes characterized CR+nCR vs NR patients in the t(4;14) positive subgroup. At the opposite, the differential expression of 3182 genes characterized CR+nCR vs NR patients in the t(4;14) negative subgroup. 271 genes which were common to the two groups of genes were excluded from the list of genes found to be differentially expressed in t(4;14) positive patients who responded to VTD. Among these patients, we observed the de-regulated expression of genes involved in cell cycle progression (e.g. MDM2, CDK6 and SMAD2), Wnt signalling pathway (e.g. FZD7, WNT10A, MMP7,WNT2B, WNT6, WNT9A and DAAM2), and Hedgehog signalling pathway (GAS1, STK36 and GLI1). Overall, genes involved in cell cycle progression resulted over-expressed, thus suggesting a more aggressive phenotype of t(4;14) positive plasma cells of responder patients; nevertheless, the overall down-regulation of genes involved in Wnt and Hedgehog signalling pathways (known to be involved in the maintenance of a putative tumoral stem cell compartment) might mitigate this phenotype and predispose t(4;14) positive plasma cells to more favourably respond to VTD induction therapy. Supported by: BolognAIL, Fondazione Carisbo, Progetto di Ricerca Finalizzata (M.C). Disclosures: No relevant conflicts of interest to declare.