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BackgroundDignity is a basic principle of palliative care and is intrinsic in the daily practice of professionals assisting individuals with incurable diseases. Dignity Therapy (DT) is a short-term intervention aimed at improving the sense of purpose, meaning and self-worth and at reducing the existential distress of patients facing advanced illness. Few studies have examined how DT works in countries of non-Anglo Saxon culture and in different real-life settings. Moreover, most studies do not provide detailed information on how DT is conducted, limiting a reliable assessment of DT protocol application and of its evaluation procedure.The aim of this study was to assess the feasibility and acceptability of a nurse-led DT intervention in advanced cancer patients receiving palliative care.MethodThis is a mixed-method study using before and after evaluation and semistructured interviews. Cancer patients referred to a hospital palliative care unit were recruited and provided with DT. The duration of sessions, and timeframes concerning each step of the study, were recorded, and descriptive statistical analyses were performed.The patients' dignity-related distress and feedback toward the intervention were assessed through the Patient Dignity Inventory and the Dignity Therapy Patient Feedback Questionnaire, respectively. Three nurses were interviewed on their experience in delivering the intervention, and the data were analyzed qualitatively.ResultsA total of 37/50 patients were enrolled (74.0%), of whom 28 (75.7%) completed the assessment. In 76.7% of cases, patients completed the intervention in the time limit scheduled in the study. No statistically significant reduction in the Patient Dignity Inventory scores was observed at the end of the intervention; most patients found DT to be helpful and satisfactory. Building opportunities for personal growth and providing holistic care emerged among the facilitators to DT implementation. Nurses also highlighted too great of a time commitment and a difficult collaboration with ward colleagues among the barriers.ConclusionsOur findings strongly support the acceptability, but only partially support the feasibility, of nurse-led DT in advanced cancer patients in a hospital setting. Further research is needed on how to transfer the potential benefits of DT into clinical practice.Trial registrationRetrospectively registered on ClinicalTrial.govNCT04738305.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening microangiopathy with a heterogeneous and largely unpredictable course. It is caused by ADAMTS13 deficiency, that can be either congenital or due to anti-ADAMTS13 autoantibodies development. ADAMTS13 deficiency is necessary but not always sufficient to cause acute clinical manifestations and trigger factors may be needed. We report the case of a woman diagnosed with congenital TTP in her adulthood, presenting with anti-ADAMTS13 autoantibodies in acute phase during ticlopidine consumption. Noteworthy, the two ADAMTS13 mutations identified in this patient are novel: one is a splice-site mutation located in intron 11 (c.1308+2_5delTAGG) and the other is a point missense mutation in exon 29 (c.4184T>C leading to p.Leu1395Pro substitution). Since congenital TTP is an extremely rare disease and drug-induced TTP is an uncommon side effect of treatment with ticlopidine, the simultaneous occurrence of both mechanisms of disease in one patient is exceptional. This case represents TTP as a multifactorial disease, with ADAMTS13 genetic abnormality and environmental exposures acting together in determining individual clinical phenotype.

Several trials comparing the efficacy of standard melphalan and prednisone (MP) therapy with MP plus thalidomide (MPT) in elderly patients with multiple myeloma (MM) have been reported, with inconsistent results. The primary goal of our study was to evaluate the efficacy and toxicity of MP versus MPT in newly diagnosed patients with MM who were transplant-ineligible or over age 65. A total of 135 patients were enrolled. Either minimal response or better or partial response or better were more frequent with MPT treatment (p = 0.001). After a median follow-up of 30 months, median progression-free survival (PFS) and overall survival (OS) were 33 and 52 months for MPT versus 22 and 32 months for MP, respectively. The comparison showed a significant advantage for MPT versus MP in PFS (p = 0.02) and only a trend for OS (p = 0.07). Severe adverse events were observed more frequently with MPT. In conclusion, our results show an improved activity of MPT at a cost of increased toxicity. We believe that MPT can be considered one of the new standard of care for elderly or transplant-ineligible patients with MM.

Background: Venous thromboembolism (VTE) is a major complication of myeloma therapy recently observed with the increasing use of up-front thalidomide and dexamethasone (thal–dex). The pathogenesis of thal-induced VTE is not well recognized, and the role of prothrombotic factors, especially of thrombophilic abnormalities, is not yet determined. Material and methods: Two hundred and sixty-six patients with newly diagnosed multiple myeloma (MM) were primarily treated with thal–dex in preparation for subsequent high-dose therapy and autologous stem-cell transplantation. Out of these 266 patients, 190 were evaluated for thrombophilic alterations at baseline, and 125 of them were also re-assessed after thal–dex therapy. Results: The presence of genetic thrombophilic polymorphisms among patients with MM was superimposable to that of normal controls and was associated with a twofold increase in the relative risk of VTE. aAPCR and elevated factor VIII levels were frequent, albeit transient, alterations and were not associated with a significant increase in the risk of VTE. Two hundred and forty-six patients received a thromboprophylaxis with fixed low-dose warfarin (1.25 mg/day) during thal–dex therapy. Of these patients (or 10.6%), 26 had symptomatic VTE events. Their patients-years rate of VTE (35.5%) was significantly lower in comparison with the 86.2% rate recorded among the first 19 patients who initially entered the study and did not receive any kind of thromboprophylaxis (P = 0.043). Conclusions: On the basis of these data, a baseline thrombophilic work up is not recommended in patients with receiving up-front thal–dex. For these patients, fixed low-dose warfarin may be a valuable prophylaxis against VTE.

Purpose To describe the clinical, morphologic, and immunohistochemical features of a case of paranasal natural killer/T-cell lymphoma (NKTL) with ocular involvement. Case report In March 2005 the patient presented with a maxillary sinusitis and upper nasal obstruction. In July she underwent a nasal computed tomography (CT) scan and multiple biopsies of the granulomatous tissue in the nasal fossae. The diagnosis was NK/T non-Hodgkin’s lymphoma nasal type, stage IV A. Afterwards she presented anterior uveitis. In September after the diagnosis of lymphoma the patient underwent a bone marrow biopsy and thoracic and abdominal CT scan. An ophthalmic examination including visual acuity assessment and fundoscopic examination was made. In October she started chemotherapy cycles. Maxillary CT scan and ophthalmic examinations were performed during the cycles. In January 2006 after severe recurrences of panuveitis a diagnostic vitrectomy was performed. Results A diagnosis of T-lymphoma cells in the vitreous was made; the tumor was most likely originating from her paranasal NKTL. The condition of the patient deteriorated rapidly and she expired on February 2006. Conclusions Nasal and paranasal sinus lymphomas are rare, but aggressive diseases with a tendency to invade tissues and spread to CNS, including the eye. Ocular manifestations prior to systemic ones may be useful to monitor the response to therapy.

Over a period of 28 months, we observed five cases of osteonecrosis of the jaw (ONJ) in cancer patients treated with bisphosphonates (BP) at our institution. This prompted us to undertake a retrospective, multicenter study to analyse the characteristics of patients who exhibited ONJ and to define the frequency of ONJ in multiple myeloma (MM). We identified 35 cases in Gruppo Italiano Studio Linfomi centers during the period 2002 - 05. The median time from cancer diagnosis to the clinical onset of ONJ was 70 months. In these 35 cases of ONJ, 24 appeared 20 - 60 months after starting BP treatment. The time for the onset of ONJ was significantly shorter for patients treated with zoledronic acid alone than for those treated with pamidronate followed by zoledronic acid. The frequency of ONJ in the MM group during the study period was 1.9%, although the nature of the present study may have resulted in an underestimation of ONJ cases. Our analysis strongly suggested an association between the use of BP and the occurrence of ONJ, although we were unable to identify any definite risk factors with a retrospective study. The most frequently ONJ-associated clinical characteristics were chemotherapy treatment, steroid treatment, advanced age, female sex, anemia, parodonthopaties/dental procedures and thalidomide (in the case of MM patients).

We performed a molecular study aimed at identifying a gene expression profile (GEP) signature predictive of attainment of at least near complete response (CR) to thalidomide-dexamethasone (TD) as induction regimen in preparation for double autologous stem cell transplantation in 112 younger patients with newly diagnosed multiple myeloma. A GEP supervised analysis was performed on a training set of 32 patients, allowing to identify 157 probe sets differentially expressed in patients with CR versus those failing CR to TD. We then generated an eight-gene GEP signature whose performance was subsequently validated in a training set of 80 patients. A correct prediction of response to TD was found in 71 % of the cases analyzed. The eight genes were downregulated in patients who achieved CR to TD. Comparisons between post-autotransplantation outcomes of the 44 non-CR-predicted patients and of the 36 CR-predicted patients showed that this latter subgroup had a statistically significant benefit in terms of higher rate of CR after autotransplant(s) and longer time to progression, event-free survival, and overall survival. These results can be an important first step to identify at diagnosis those patients who will respond more favourably to a particular treatment strategy.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening microangiopathy with a heterogeneous and largely unpredictable course. It is caused by ADAMTS13 deficiency, that can be either congenital or due to anti-ADAMTS13 autoantibodies development. ADAMTS13 deficiency is necessary but not always sufficient to cause acute clinical manifestations and trigger factors may be needed. We report the case of a woman diagnosed with congenital TTP in her adulthood, presenting with anti-ADAMTS13 autoantibodies in acute phase during ticlopidine consumption. Noteworthy, the two ADAMTS13 mutations identified in this patient are novel: one is a splice-site mutation located in intron 11 (c.1308+2_5delTAGG) and the other is a point missense mutation in exon 29 (c.4184TC leading to p.Leu1395Pro substitution). Since congenital TTP is an extremely rare disease and drug-induced TTP is an uncommon side effect of treatment with ticlopidine, the simultaneous occurrence of both mechanisms of disease in one patient is exceptional. This case represents TTP as a multifactorial disease, with ADAMTS13 genetic abnormality and environmental exposures acting together in determining individual clinical phenotype.

A retrospective survey was conducted over a 10-year period (1990-99) among 52 haematology divisions in order to evaluate the clinical and laboratory characteristics and outcome of patients with proven Pneumocystis carinii pneumonia (PCP) complicating haematological diseases. The study included 55 patients (18 with non-Hodgkin's lymphoma, 10 with acute lymphoblastic leukaemia, eight with acute myeloid leukaemia, five with chronic myeloid leukaemia, four with chronic lymphocytic leukaemia, four with multiple myeloma, three with myelodysplastic syndrome, two with myelofibrosis and one with thalassemia) who developed PCP. Among these, 18 (33%) underwent stem cell transplantation; only two received an oral prophylaxis with trimethroprim/sulphamethoxazole. Twelve patients (22%) developed PCP despite protective isolation in a laminar airflow room. The most frequent symptoms were: fever (86%), dyspnoea (78%), non-productive cough (71%), thoracic pain (14%) and chills (5%); a severe hypoxaemia was present in 39 patients (71%). Chest radiography or computerized tomography showed interstitial infiltrates in 34 patients (62%), alveolar infiltrates in 12 patients (22%), and alveolar-interstitial infiltrates in nine patients (16%). Bronchoalveolar lavage was diagnostic in 47/48 patients, induced sputum in 9/18 patients and lung biopsy in 3/8 patients. The diagnosis was made in two patients at autopsy. All patients except one started a specific treatment (52 patients trimethroprim/sulphamethoxazole, one pentamidine and one dapsone). Sixteen patients (29%) died of PCP within 30 d of diagnosis. Multivariate analysis showed that prolonged steroid treatment (P < 0.006) and a radiological picture of diffuse lung involvement (P < 0.003) were negative diagnostic factors.

Abstract 349 We report here on the final analysis of the multicenter phase II “Bologna 2002” study which incorporated thal-dex into double ASCT with high-dose melphalan (200 mg/m2) as front-line therapy for younger patients with symptomatic multiple myeloma (MM). By study design, thal (200 mg/day) and pulsed low-dose dex (160 mg/month, with two added 4-day courses on the first and third cycle of induction therapy) were administered from the outset until the second ASCT. The analysis was performed on an intention-to-treat basis on a total of 357 patients who were followed for a median of 43 months. Their median age was 57 years, 86% had advanced disease stage. More than 80% of the patients were screened at diagnosis for the presence of cytogenetic abnormalities (FISH) on CD138+ bone marrow plasma cells, including del(13q) (45%), t(4;14) (14%) and del(17p) (6%). The rate of at least VGPR increased from 31% after thal-dex induction therapy to 60% after the second ASCT. The final CR rate was 33% for all the patients and 44% for those who actually received pre planned double ASCT. Median TTP and PFS were 68 and 47 months, respectively, with 5-year projected rates of 45% and 33%. The 5-year projected OS rate was 65%. TRM after the first and second ASCT was 0.5% and 2%, respectively. Median OS after relapse or progression was 30 months, suggesting that short-term thal exposure had no adverse influence on response to salvage therapies. The quality of response following ASCT(s) influenced clinical outcomes. In particular, patients achieving CR had significantly longer PFS and OS than patients in VGPR (PFS: median 68 vs 48 months, respectively, P=0.04; 5-year projected OS 84% vs 72%, respectively, P=0.02). Similarly, patients in VGPR had better outcomes compared with patients achieving PR (P=0.02 and 0.04 for PFS and OS comparisons, respectively). In a multivariate analysis, best response (at least VGPR) ever achieved and low beta2-m were the most important variables significantly extending TTP (P=0.04), PFS (P=0.000) and OS (P=0.003). Additional variables predicting for prolonged PFS were the absence of del(13q) (P=0.002) and del(17p) with or without t(4;14)(P=0.03). OS was favourably influenced also by IgG isotype (P=0.04) and absence of high-risk cytogenetic abnormalities [del (17p) +/- t(4;14)(P=0.03)]. A case match comparison of 135 patients enrolled in “Bologna 2002” study with an equal number of pair mates included in the previous “Bologna 96” study of double ASCT without thal confirmed the benefits from the addition of thal-dex to double autotransplantation in terms of rate (P=0.001) and duration (p Disclosures: Off Label Use: Thalidomide was incorporated into up-front treatment for patients with newly diagnosed multiple myeloma.

Abstract 351 Introduction A phase III study of melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) incorporating thalidomide (T) and dexamethasone (D) with or without the addition of bortezomib (V) as first-line therapy for younger (≤65 years) patients (pts) with newly diagnosed multiple myeloma (MM) is currently being conducted by the Italian Myeloma Network GIMEMA. Patients and Methods By study design, pts were random assigned to receive three 21-d cycles of either bortezomib-thalidomide-dexamethasone (VTD) (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or thalidomide-dexamethasone (TD) (both drugs at the same dose and schedule than in VTD) as induction therapy in preparation for ASCTs. Two 35-d cycles of either VTD or TD were given as consolidation therapy following ASCTs (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle). Primary study end point was the rate of high-quality responses [immunofixation negative complete response (CR) and ≥very good partial response (VGPR)] to induction therapy. Secondary study end points included response to, and toxicity of, subsequent treatment phases (including first and second ASCTs, and consolidation therapy), progression-free survival (PFS) and overall survival (OS). Analyses were intent to treat. All the 474 pts were evaluated for response to, and toxicity of, induction therapy. Responses reported by study investigators were centrally reassessed to confirm CR and VGPR; pts reported as complete responders but in whom bone marrow aspirate was not evaluable or not performed were reassessed as in VGPR. The VGPR category included the subcategories of near CR and VGPR. Results The study was closed to pts accrual after a total of 480 pts were enrolled; of these, 6 failed inclusion criteria and the remaining 474 were randomized to the VTD (n=236) or TD (n=238) arm. The mean total dose of V received in induction therapy was 14.7 mg (or 94% of that planned). Grade 3 peripheral neuropathy (PN) and skin rash (SR) were reported more frequently with VTD induction therapy than with TD (PN: 9.7% vs 2.1%, respectively; P Conclusions Incorporation of VTD into double ASCT for newly diagnosed MM resulted in a significant improvement in clinical outcomes (CR, ≥VGPR, PFS) in comparison with TD and double autotransplantation. Superior benefit with VTD and double ASCT in comparison with the control group was maintained in pts at high risk of progression or death, including those with t(4;14) and/or del(17p). Disclosures: Cavo: Celgene: Honoraria; Ortho Biotech, Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Honoraria; Novartis: Honoraria.

Purpose We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM). Patients and Methods A total of 321 patients were enrolled onto the study and were randomly assigned to receive either a single course of high-dose melphalan at 200 mg/m2 (arm A) or melphalan at 200 mg/m2 followed, after 3 to 6 months, by melphalan at 120 mg/m2 and busulfan at 12 mg/kilogram (arm B). Results As compared with assignment to the single-transplantation group (n = 163 patients), random assignment to receive double ASCT (n = 158 patients) significantly increased the probability to attain at least a near complete response (nCR; 33% v 47%, respectively; P = .008), prolonged relapse-free survival (RFS) duration of 18 months (median, 24 v 42 months, respectively; P < .001), and significantly extended event-free survival (EFS; median, 23 v 35 months, respectively; P = .001). Administration of a second transplantation and of novel agents for treating sequential relapses in up to 50% of patients randomly assigned to receive a single ASCT likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplantation group (43%; P = .90). Transplantation-related mortality was 3% in arm A and 4% in arm B (P = .70). Conclusion In comparison with a single ASCT as up-front therapy for newly diagnosed MM, double ASCT effected superior CR or nCR rate, RFS, and EFS, but failed to significantly prolong overall survival. Benefits offered by double ASCT were particularly evident among patients who failed at least nCR after one autotransplantation.

Cryptococcosis is an important cause of morbidity and death in immunocompromised patients. The aim of this study was to evaluate clinical and laboratory characteristics, and outcome of patients with cryptococcosis complicating hematologic diseases.This was a retrospective study, conducted over a ten-year period (1993-2002) in 21 hematology divisions, in tertiary care or university hospitals.This study evaluated 17 patients with hematologic diseases who developed cryptococcosis. Possible risk factors recognized before the onset of the infection were: administration of steroids for the underlying malignancy (6 patients), diabetes mellitus (4 patients), cutaneous lesions (2 patients) and autoimmune disease, hepatic cirrhosis, chronic renal failure and exposure to pigeons (1 patient each). Five patients received prophylaxis, consisting of fluconazole in 2 cases. Fever, neurological and respiratory signs developed according to the primary sites of infection (5 blood, 5 central nervous system, 4 lung, and 1 each in gut, skin and mouth). Diagnosis was made by positive microbiological culture, antigen detection in serum or cerebrospinal fluid, or polymerase chain reaction. All patients started specific treatment (fluconazole, 7 patients; amphotericin-B deoxycolate or liposomal amphotericin-B, 10 patients). Two patients died from cryptococcosis within 30 days after diagnosis.Cryptococcosis in patients with hematologic malignancies is a rare complication. In neutropenic patients, it is less fatal than other fungal infections (i.e. aspergillosis or candidemia). Specific treatment, started promptly, positively influences the outcome.

Background The combination of immunomodulatory drugs (IMiDs(r)) and alkylating agents have significantly improved outcomes of patients with relapsed or refractory multiple myeloma (RRMM). Bendamustine, an agent sharing properties of alkylators and purine analogous, and lenalidomide, an immunomodulator drug, are highly effective for the treatment of lymphoprolipherative disorders. Some clinical trials have shown good responses to the combination of bendamustine with steroids and novel agents (thalidomide, lenalidomide and bortezomib) for the treatment of RRMM (Knop S 2005, Lentzsch S 2012, Pönisch W 2013), but further research is needed to confirm the best combination, the optimal schedule of administration, and to better define the safety profile. Method A multicenter phase I/II trial tested the combination of escalating doses of bendamustine and lenalidomide, and a fixed dose of dexamethasone (BdL) in repeating 4-weeks cycles as treatment for RRMM. The drug dosages were chosen taking into account the haematological toxicity of both, and that patients were heavily pretreated. The phase I trial was conducted using a 3+3 cohort design beginning at a dose level 0 of intravenous bendamustine 40 mg/m²/day, days 1 and 2, oral lenalidomide 10 mg/day, days 1-21 and oral dexamethasone 40 mg/day, days 1, 8, 15, and 22 every 4 weeks. Patients were treated for 4 cycles + 2 cycles if the response was stable disease (SD) or better. In the phase II study patients were treated at the maximum tolerated dose (MTD) to evaluate the antimyeloma activity of BdL. Endpoints of the study included safety profile, overall response rate (ORR), progression-free survival (PFS), duration of remission (DR) and overall survival (OS). Results A total of 41 patients (17 in phase I, and 24 in phase II) were enrolled between October 2011 and July 2013. Four patients withdrew their informed consent: 3 before starting treatment and 1 after the fifth cycle. Twenty-eight out of 37 are currently evaluable. Median age of these patients was 68 (43-87 years), with a male/female ratio of 12/16. Sixteen patients had IgG MM, 10 had IgA, and 2 patients had light chain MM. Median number of previous treatments was 3; 9 patients were previously treated with thalidomide and 6 with lenalidomide; 19 with bortezomib and 11 underwent autologous stem cell transplant. The MTD established by the phase I study was dose level 0. To date, with a median follow up of 10 months, ORR is 50% (3 CR, 2 VGPR, 9 PR) and 1 SD. The median OS has not been reached yet. One-year OS is 78% (95% confidence interval [CI], 57%-89%). Median PFS is 10 months (95% CI, 5-12 months) with one-year PFS of 40% (95% CI, 21%-59%). Median duration of remission is 9.6 months with one-year DR of 44% (95% CI, 12%-73%; Figure 1). Toxicity data was available for 32 pts. Grade 3/4 adverse events (AEs) observed in ≥ 10% of patients included neutropenia, thrombocytopenia and anemia. The major non-hematological toxicity was renal dysfunction (6%). A total of 8 pts died during the study: 5 due to toxicity and 3 for progression of disease. Conclusions This study confirms that the combination of bendamustine with lenalidomide and low dose dexamethasone is effective in RRMM patients, even when administered after regimens containing novel agents. The dose of bendamustine in our study is lower (40 mg vs. 75 mg) that of previously published data (Knop S 2005, Lentzsch S 2012, Pönisch W 2013). However, we would like to emphasize that in our both phase I and phase II study we observed a consistent toxicity even utilizing 40 mg of bendamustine and 10 mg of lenalidomide. The toxicity was mainly hematological. Thus far, age, number of previous treatments, or the previous use of alkylating agents did not correlate with observed toxicity. In conclusion with a 50% ORR and 3 CR this is a very promising therapeutic option in RRMM requiring careful management of the patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 4210 In a previous analysis performed with a median follow-up of 36 months (mos), superior CR/nCR rates and extended PFS were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autotransplantation (ASCT) for newly diagnosed myeloma (MM). Here we report an updated analysis of that study, including a detailed analysis of outcomes after relapse or progression (R/P), an important issue for patients (pts) who received up-front a triplet novel agent-based therapy incorporated into ASCT. After a median follow-up of 52 mos, continued TTP and PFS benefits with VTD vs TD were demonstrated, while no difference in OS was seen between the two arms. Median PFS for pts randomized to the VTD arm was 56 mos vs 42 mos for those assigned to TD (HR=0.64, p=0.001). Similarly to PFS, median TTP for pts in the VTD group was longer than in the TD group (57 vs 45 mos, HR=0.63, p=0.0006), reflecting a 37% reduction in the risk of R/P with VTD. The probabilities of R/P in the VTD and TD arms were 41% vs 55% (p=0.002). In comparison with the VTD-treated group, a higher percentage of pts in the TD arm required the immediate start of salvage therapy after symptomatic R/P was documented (67% vs 82.5%). By the opposite, the fraction of pts with asymptomatic R/P that did not require any antimyeloma therapy until the cut-off date for the analysis was higher in the VTD arm compared with the TD-treated group (33% vs 17.5%, p=0.016). In these pts, the median interval from the date of R/P to the cut-off date for the analysis was 7 mos for the TD-treated group vs 17 mos for the VTD-treated group. Median time to subsequent antimyelomatherapy (defined as the interval between start of induction therapy and administration of the first dose of second-line therapy) was significantly longer for pts who experienced R/P in the VTD arm in comparison with pts who progressed in the TD arm (35 vs 29 mos, p=0.018). The associated interval between last administration of front-line therapy (e.g. consolidation for pts who received the entire treatment program or every other treatment before consolidation for those who discontinued earlier) and first administration of second-line therapy (salvage therapy-free interval) was 22.5 mos for the VTD-treated group vs 15 mos for the TD-treated group (p=0.009). Both bortezomib and lenalidomide were the most frequently used agents at the time of R/P (82% of all cases), while only 18% of pts were treated with conventional cytotoxic drugs. As expected, the majority of pts in the TD arm received a second-line therapy that included bortezomib (70%), while lenalidomide-dexamethasone was received by 10% of pts. By the opposite, in the VTD arm both bortezomib- and lenalidomide-based salvage therapies were equally distributed (41% vs 39%). The probability to achieve at least a partial response after second-line therapy including bortezomib was 60% for pts with prior exposure to VTD vs 63% for those randomized to TD. No difference in post-R/P OS was demonstrated between VTD-treated and TD-treated subgroups of pts who received bortezomib-based salvage therapy after R/P (2-yr estimates: 48% vs 53%, p=0.59). In the overall population, post-R/P OS was significantly shorter for pts who received salvage therapy with conventional cytotoxic drugs (2-yr estimate: 41%) in comparison with pts treated with novel agents, including bortezomib or lenalidomide (2-yr estimates: 52% and 53%, respectively) (p=0.0001). In conclusion, front-line therapy with VTD incorporated into ASCT was superior in comparison with TD plus ASCT in terms of extended TTP, PFS, time to subsequent antimyeloma therapy and salvage therapy-free interval. VTD-treated pts had a higher probability than TD-treated pts to experience long-lasting asymptomatic R/P not requiring second-line therapy. VTD-treated and TD-treated pts who subsequently received bortezomib-based salvage therapies had similar rates of response and post-R/P OS. This finding suggests that short-term exposure to VTD, as planned in our study, did not favor the selection of bortezomib-resistant clones, thus allowing to rechallenge bortezomib as (part of) second-line therapy after symptomatic R/P. Disclosures: Cavo: Janssen, Celgene, Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Di Raimondo:Celgene, Janssen: Honoraria, Speakers Bureau. Offidani:Janssen, Celgene: Honoraria. Caravita:Celgene, Janssen, Novartis, Genzyme: Honoraria. Boccadoro:Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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.

Abstract 594 Survival of patients with multiple myeloma (MM) has been extended with the introduction of autologous stem cell transplantation (ASCT). More recently, availability of highly effective novel agents has further improved patient outcomes. However, it is still the matter of debate whether a proportion of patients treated with ASCT can enjoy a long term survival, while sustaining prolonged high quality response. To address this issue and to identify those variables which were related to long-term survival, we performed a post-hoc analysis of two large prospective clinical trials of ASCT in newly diagnosed MM patients, the first one comparing single versus double ASCT and the second one incorporating thalidomide-dexamethasone (TD) into double ASCT. A total of 321 patients were randomly assigned in the first study to receive either a single or double ASCT, as previously described (Cavo M et al, JCO 2007). Three hundred and fifty seven patients were enrolled in the subsequent multicenter phase 2 study incorporating TD from the outset until the second ASCT; details of the protocol were previously reported (Cavo et al, J. Clin. Oncol 2009). Results were updated as of 30 March 2012 and compared with those previously reported. All the analyses were performed on an intention-to-treat basis. After a median follow-up of 61 months for the entire treatment population of the first study, PFS remained significantly longer with tandem versus single ASCT (median 37 vs 25 months, P= 0.012), while OS was similar in the two groups (median 71 vs 67 months). 47% and 33% of the patients in the double and single ASCT group achieved a CR+nCR (P= 0.008). Overall, in 24% and 11% of the patients, CR+nCR was sustained for more than 5 and 10 years, respectively. In a multivariate Cox regression analysis, best response (CR+nCR) ever achieved was the most important variable significantly extending PFS (P= 0.003) and OS (P=0.050); random assignment to double ASCT was an additional variable predicting for prolonged PFS(P= 0.026). After a median follow-up of 84 months from starting TD in the second study, median values of PFS and OS were 47.2 and 109.6 months, respectively. The final rate of CR+nCR was 34%, which was maintained for a median of 53 months. Overall, in 42.1% and 9.1% of the patients CR+nCR was sustained for more than 5 and 8 years, respectively. On multivariate analysis, failure to ever achieve at least CR+nCR, low Hb, high β2-m and t(4;14)±del(17p) were found to be independent variables predicting for poorer outcomes. In particular, a shorter OS was seen for patients ever lacking high-quality responses (HR: 0.35, 0.23–0.54, p Overall, 23% and 20% of patients in the first and second study were alive over 10 or 8 years, respectively (long-term survivors). Median PFS of long-term survivors in the 2 studies were 74 and 87.7 months, respectively, versus 25 and 37 months for the rest of the population (P= 0.0000). Median duration of CR+nCR were 70 and 78 months in the long-term survivors group for the first and second study, respectively, in comparison with 21 and 49 months in the remaining patients (P In conclusion, although the comparison between TD incorporated into ASCT and ASCT without thalidomide was not directly addressed by this analysis, TD + ASCT was associated with extended PFS and OS. Approximately 20% of the patients undergoing up-front ASCT can achieve long term survival (8–10 years from start of treatment), with 33% of them remaining relapse free. Attainment of sustained high-quality responses was the leading independent variable predicting for long-term OS. Prolonged survival after relapse was a contributing factor to long-term OS. Disclosures: Off Label Use: One of the 2 protocols discussed includes the use of thalidomide as induction prior to ASCT.

Abstract 1871 Introduction: In a randomized phase 3 study, the use of VTD as induction therapy prior to and consolidation therapy following double ASCT increased the rate of complete or near complete response (CR/nCR) and extended PFS in comparison with TD given as induction and post-ASCT consolidation therapy in 474 newly diagnosed MM patients (Cavo et al, Lancet 2010). However, the specific impact of VTD consolidation on improved clinical outcomes was not defined. Methods: To address this issue, we performed a per-protocol analysis of 321 patients who received the entire treatment program, including the two pre-planned cycles of consolidation therapy with either VTD (160 of 236 patients, 68%) or TD (161 of 238 patients, 68%). By study design, two 35-d cycles of VTD (V 1.3 mg/m2 on days 1, 8, 15, and 22; T 100 mg/d on days 1–35; D 40 mg on the days of and after each V administration) or TD (at the same doses as in VTD) were given as consolidation therapy to patients randomly assigned to each of the two respective induction regimens. Patient and disease characteristics at baseline were comparable in the two groups of patients. Results: The rates of CR and CR/nCR were significantly higher after consolidation therapy with VTD compared with TD (CR: 61% vs 47%; p=0.012; CR/nCR: 73% vs 61%; p=0.020). The impact of VTD consolidation on post-ASCT enhanced rates of CR and CR/nCR was confirmed by the McNemar test (CR: p=0.0009; CR/nCR: p=0.004) which conversely failed to demonstrate a significant increase in the frequencies of CR (p=0.052) and CR/nCR (p=0.110) with TD consolidation therapy. The absolute probability of upgrading from less than CR before consolidation to CR after consolidation was 31% with VTD and 17% with TD (Pearson chi-square test: p=0.03). Ninety six percent of patients who upgraded from less than CR to CR after VTD consolidation were in nCR (44%) or VGPR (52%) before starting consolidation therapy. A landmark analysis (with the landmark set as the start of consolidation therapy) was performed to compare time to progression (TTP), PFS, and overall survival (OS) between treatment groups. With a median follow-up of 30 months, the estimated 3-year probability of relapse or progression was 38% with VTD and 52% with TD (p=0.039 by Kaplan-Meier analysis) (HR: 0.68, 95% CI: 0.47–0.98, p=0.041). PFS was significantly longer for patients receiving VTD consolidation than for those treated with TD (3-year estimates: 62% vs 46%; p=0.025) (HR: 0.66, 95% CI: 0.46–0.95, p=0.027), a gain particularly evident for patients who failed to achieve CR after ASCT (3-year PFS estimates: 66% vs 43%; HR: 0.54, 95% CI: 0.32–0.91, p=0.022). Superior PFS with VTD vs TD consolidation was retained across poor prognosis subgroups, including patients with t(4;14) and/or del(17q) (HR: 0.44, p=0.004), del(13q) (HR: 0.44, p=0.002), β2-microglobulin >3.5 mg/L (HR: 0.57, p=0.025), lactate dehydrogenase >190 U/L (HR: 0.57, p=0.005), or ISS stage 2 and 3 (HR: 0.57, p=0.021). In a multivariate regression analysis, the most important and independent variables positively correlated with PFS were VTD consolidation therapy (p=0.002), double ASCT (p=0.001), low β2-microglobulin (p Conclusions: In comparison with TD, post-ASCT consolidation therapy with the triplet VTD regimen significantly increased the rates of CR and CR/nCR, and extended landmarked TTP and PFS. Superior PFS with VTD consolidation was maintained across poor prognosis subgroups, including those with advanced ISS stage and/or high-risk cytogenetic profiles. In a multivariate regression analysis VTD consolidation was confirmed to be an independent variable favorably affecting PFS. The superior activity seen with VTD versus TD as induction therapy before ASCT was retained despite the same triplet regimen being used as post-ASCT consolidation. Disclosures: Cavo: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Genzyme: Honoraria. Off Label Use: Bortezomib and Thalidomide as post autotransplantation consolidation therapy in myeloma. Patriarca:Schering-Plough: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Roche: Honoraria. Petrucci:Celgene: Honoraria; Janssen: Honoraria. Di Raimondo:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Palumbo:Merck: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Offidani:Celgene: Honoraria; Janssen: Honoraria. Baccarani:Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract 1867 Background: In recent years, there have been major advances in the treatment of multiple myeloma (MM) as patients now have treatment options that greatly improve clinical outcomes. Many publications have described the safety of anti-myeloma drugs in the clinical trial setting. However, very few have addressed the issue of tolerability of these agents in a real-world clinical setting. Lenalidomide is an effective treatment option for MM and is currently approved by the EMA and US FDA for the treatment of MM patients who have received at least 1 prior therapy. Here we analyze the tolerability of 3 common novel agent-based anti-myeloma therapies in daily clinical practice. Methods: This observational post-authorization safety study was designed to characterize the safety profile of lenalidomide and to compare the incidence of adverse events (AE) with those occurring in patients receiving other anti-myeloma treatments. Patients entering the study had previously received at least 1 prior therapy and were commencing a new treatment for their relapsed/refractory MM (RRMM). Patients were enrolled into the Lenalidomide Cohort (lenalidomide plus dexamethasone) or the Background Cohort (all other treatments) based on investigator's discretion. Thromboprophylaxis was allowed, but not required. Results: As of July 2011, 2201 RRMM patients in 265 institutions in 17 European countries were enrolled. 1500 received lenalidomide, 538 bortezomib, 90 thalidomide, and 73 received other therapies or had missing data. 75 patients from the Background Cohort crossed over to receive lenalidomide. Median follow-up was 20.7 weeks (range, 0.1–125.7 weeks). Overall, the median age was 69 years (range, 29–92) and 55% were male. Most patients had a good performance status (ECOG 0–1) but 18% had an ECOG score of 2–4. The median number of previous treatment lines was 2 (1–6), 51.5% had 2 previous lines and 24% had 3 or more. Baseline characteristics across treatment groups were similar. Patients receiving lenalidomide had a median treatment duration of 4.4 months; patients receiving bortezomib and thalidomide had 3.4 months and 3.7 months, respectively. NCI grade 3/4, serious and life threatening AEs are presented in the table. Venous thromboembolism was experienced in 5% of lenalidomide-treated patients (3% had grade 3/4); 0.7% of bortezomib-treated patients (0.6% had grade 3/4); 1 (1%) thalidomide-treated patient had grade 3/4. Peripheral neuropathy was observed in 10% of lenalidomide-treated patients (1% had grade 3/4); 28% of bortezomib-treated patients (4% had grade 3/4); and 21% of thalidomide-treated patients (2% had grade 3/4). Ten (0.5%) invasive second primary malignancies (SPM) were reported across all treatment groups; 5/1500 (0.3%) patients treated with lenalidomide, 4/538 (0.7%) with bortezomib, and 1/90 (1%) with thalidomide. Three cases of second primary hematologic malignancies (lenalidomide, 2; bortezomib, 1; thalidomide, none) and 7 cases of second primary solid tumors (lenalidomide, 3; bortezomib, 3; thalidomide, 1) were observed. Additionally in the lenalidomide group, 1 patient each developed a non-invasive basal cell carcinoma and a non-invasive fibrous histiocytoma. All of these patients were heavily pre-treated and most had received autologous stem cell transplantation to support high-dose melphalan during the course of their disease. 51% of patients in the lenalidomide group discontinued therapy while 65% and 71% discontinued bortezomib and thalidomide treatments, respectively. Primary reasons for discontinuation were adverse events (lenalidomide, 13%; bortezomib, 14%; thalidomide, 18%) and disease progression (lenalidomide, 15%; bortezomib, 13%; thalidomide, 17%). Overall, 1% of patients died due to an adverse event suspected to be related to drug (lenalidomide, 1%; bortezomib, 0%; thalidomide, 1%). Conclusion: Consistent with previous reports, lenalidomide is generally well tolerated. With the exception of peripheral neuropathy, adverse events in this group of patients treated in daily clinical practice appeared similar across treatment groups. Disclosures: Cavo: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Symeonidis:Novartis Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Genzyme: Research Funding; Pfizer: Research Funding; Gilead: Consultancy, Research Funding. Bird:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Genzyme: Membership on an entity's Board of Directors or advisory committees. Bacon:Celgene Corporation: Employment. Rosettani:Celgene Corporation: Employment. Kueenburg:Celgene Corporation: Employment. Minton:Celgene Corporation: Employment, Equity Ownership.

Abstract 5134 BACKGROUND: Bisphosphonates (BP) are standard supportive care in patients affected by symptomatic multiple myeloma (MM) with skeletal lesions. Despite the long term use of BP in the clinic, many of the effects of this category of drugs and their optimal schedule of administration are still matter of debate. In the recent past the identification of osteonecrosis of the jaw induced clinicians and researchers to reevaluate the schedule of administration of BP in myeloma, questioning about their effects on other cells than osteoclasts. Therefore a better definition of risks and benefits of anti-catabolic agents may help addressing future studies in this field. Recently a growing number of publications alerted orthopedics and endocrinologists about a rare but serious event called “atypical low energy fractures” (LEF) in patients affected by osteoporosis treated with long term BP (1–3). LEF refer to stress fractures, mainly localized in the subtrochanteric region, spontaneous or secondary to minor trauma, often preceded by local pain, with specific radiologic patterns and sometimes delayed healing. Localizations in bones different than femur have been reported. Still debated is the association with BP and the pathophysiology of this condition. So far three cases of fractures with the characteristics of LEF have been described in MM patients. METHODS: in order to evaluate the possible existence of other cases of LEF in patients with MM we started a retrospective survey in hematological centers, collecting the cases of MM followed by each center between January 2005 and December 2010, and any case of atypical fracture not related to MM or major trauma. Inclusion criteria for LEF were so defined: diagnosis of MM; treatment with BP; fractures induced by minor trauma or spontaneous, not associated with MM localization; radiological aspect of stress fracture; +/− prodromic pain. Central revision of patients history and radiology will be conducted with the support of an orthopedic in the patients with atypical fractures, followed by bone histomorphometry on bone marrow biopsy. RESULTS: The study is ongoing. At present seven centers reported a total of 1065 patients affected by MM followed between 2005 and 2010 and five cases of suspect LEF. The first patient is a woman diagnosed with anaplastic myeloma in 2002, apparently in complete remission after 4 lines of treatment. In June 2008 the patient was diagnosed with an atraumatic left fracture of the fifth metatarsal bone, followed by a right metatarsal fracture one month later and second right metatarsal stress fracture in 2011. The fractures were not related to myeloma localization. Other four cases of fractures are under investigation in other two center. CONCLUSIONS: MM patients are exposed to high rate of bone fractures related to the hematological disease and at the best of our knowledge the frequency of stress fractures in this population is unknown. With the present study, over a population of more than one thousand patients, we observed five cases of possible LEF that will undergo detailed analysis through central revision of patients history, radiology and bone histomorphometry with the aim to identify individual risk factors. Despite LEF is a rare and still controversial condition, the identification of individual risks to develop fractures not secondary to MM, may help clinicians tailoring the treatment for bone disease, much needed in an era of new drug discoveries for bone treatment. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria.

Abstract 1369 Introduction: Single-agent cladribine (2CdA) given intravenously or subcutaneously (sc) is highly effective in Hairy cell leukemia (HCL). However, HCL patients are projected to progress in their life-span or, in a minority, are refractory and may benefit from other treatment strategies. Parameters predicting efficacy of (sc)2CdA in HCL are scarcely known. Aims: In a national multicentre clinical trial (EudraCT code: ICGHCL2004) we prospectively sought parameters able to predict efficacy of sc2CdA in classic HCL requiring first treatment (1987 Consensus Criteria). Methods: Clinical data and samples were collected centrally for diagnostic revision according to the WHO criteria and for molecular analyses prior to treatment. Tumor IGH and TP53 analyses or Genome-wide DNA profiling was performed in the cases with >10% or >50% hairy cells (HC) in the test sample, respectively (Forconi, Blood 2009). Patients entering the study received 0.5–0.7 mg/kg sc2CdA as a single course. Efficacy endpoints were response to sc2CdA, treatment free interval (TFI), relapse free survival (RFS), and overall survival (OS). Responses were assessed on month 2 and 6 after treatment and defined according to the 1987 Consensus criteria. Complete Remissions (CR) and Partial Remissions (PR) were rated as beneficial responses (CR/PR), while minor Responses (mR) and No Responses (NR) were rated as failures (mR/NR). TFI was measured in all patients from sc2CdA initiation to time of new treatment requirement. RFS was measured in patients with CR/PR from sc2CdA initiation to relapse. OS was measured from sc2CdA initiation to death. Results: Of 148 patients, 116 were males (78,4%). Median values were: age 52 years (range 30–83), splenomegaly below costal margin 2 cm (0-16), hemoglobin 11,8 (5-17 g/dL), PLT 77×10e9/L (14-255), WBC 2,7×10e9/L (0,7-48), HC 0,2×10e9/L (0-38). Serum B2microglobulin was twice above upper limit (B2M>2X) in 9/122 patients (7,4%), IGH unmutated (UM) in 7/62 (11,3%) and TP53 mutated (mutTP53) in 2/62 (3,2%). Onehundred-forty patients (94,6%) had a CR/PR (101 CR, 68,2%; 39 PR, 26,4%) and 8 (5,4%) a mR/NR (5 mR, 3,4%; 3 NR, 2%). Risk factors of sc2CdA failure were splenomegaly (p=.001, best-cutoff> 3 cm bcm by ROC and Youden's Test), WBC (p10×10e9/L), HC counts (p5×10e9/L), and B2M>2X (p=.013). In 62 patients investigated for molecular features, UM-IGH and TP53 were confirmed as risk factors for mR/NR (p10×10e9/L (p5×10e9/L (p5×10e9/L, spleen>3cm, UM-IGH and mutTP53), UM-IGH (HR=8.1, 95%CI 1.7–38.1, p=.008, median TFI=8.5 months), high HC (HR=6.9, 95%CI 1.5–31.6, p=.012, TFI=27,4 months) and splenomegaly (HR=3.7, 95%CI 1.1–12.8, p=.039, TFI=49,3 months) scored as independent risk factors. Quality of response also predicted risk of short TFI (NR=mR>PR>CR, p5×10e9 (p=.016) and PR (p=.001)as risk factors of short RFS. Cox multivariate analysis revealed PR as the sole independent risk factor of relapse after a median of 46 months (HR=4.5, 95%CI 1,7-12,3, p=.003). 2CdA dose schedule was among other factors that did not associate with TFI or RFS. Conclusion: This data confirm that sc2CdA has potent activity in HCL. Tumor UM-IGH status, splenomegaly, high HC count (or leukocytosis) are confirmed as independent risk factors of treatment failure and rapid progression. RFS analysis identify PR as the sole independent factor of relapse risk in the patients initially responsive to sc2CdA. This analysis may have important implications for the selection of HCL patients that will require treatments alternative to single-agent 2CdA. Disclosures: No relevant conflicts of interest to declare.

Abstract 1939 Aim and Background: Lenalidomide plus dexamethasone was EMEA approved in 2007 for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Subsequently, an observational patient cohort study was implemented to characterize the safety profile of lenalidomide in clinical practice, and to place the incidence of adverse events (AEs) into context with those occurring in patients with MM receiving other treatments second line or later. A secondary objective of the study was to assess the evolution or resolution of peripheral neuropathy (PN) in patients taking lenalidomide, who had pre-existing PN at baseline. Methods: Data were collected prospectively from 1,011 patients with MM, in 177 institutions in 15 European countries. Patients had received at least one prior therapy and were commencing a new treatment with prescribed medication in accordance with normal clinical practice at the time of enrollment. No additional treatments or investigations outside of normal clinical practice were required. PN status was assessed by physicians according to their normal clinical practice. PN was recorded at baseline and, if present, the status was subsequently recorded at all following data collection points until the patient discontinued study treatment. For those patients who did not have PN at baseline, any new occurrence of PN was documented as an AE. Data cutoff for this analysis was May 4, 2010. Results: Of the 1,011 patients who entered the study, 658 patients started lenalidomide-, 207 bortezomib-, and 53 thalidomide-based therapies; 43 patients commenced other therapies and 50 had missing data. Median Kaplan-Meier estimated treatment duration was 6.4 months for lenalidomide, 3.8 for bortezomib, and 4.8 for thalidomide. Baseline PN was reported in 39% (254/658) of patients in the lenalidomide cohort: 22% (144/658) were reported to be due to previous bortezomib and 18% (118/658) were due to previous thalidomide. In the bortezomib cohort 21% (43/207) had baseline peripheral neuropathy: 3% (6/207) were reported due to previous bortezomib and 13% (27/207) due to previous thalidomide. Baseline PN due to prior vincristine use was low (2% of patients), and non-drug induced PN was between 4–6% in the three cohorts overall. Observed PN in the lenalidomide cohort was 42% (89/213) at baseline and 29% (62/213) at 4 months, compared with 26% at baseline (16/61) and 23% (14/61) at 4 months in the bortezomib cohort. There was no change over the 4 month period in the thalidomide cohort (16% 3/19). Treatment discontinuations due to AEs were highest in the thalidomide cohort (24.5%), and similar in the lenalidomide (14.1%) and bortezomib (15.5%) cohorts. However, patient discontinuations due to PN were six times higher in the bortezomib (4.8%) cohort compared with the lenalidomide cohort (0.8%). The incidence of drug-related PN and grade 3* or 4** drug-related PN was four times lower in the lenalidomide cohort compared with the bortezomib cohort. Conclusion: In this unselected group of patients taken from normal clinical practice and treated with lenalidomide-, bortezomib-, or thalidomide-based therapies, lenalidomide demonstrated a low incidence of drug-related PN. A high proportion of patients commencing treatment with lenalidomide had baseline PN due to their previous anti-myeloma therapy. Preliminary data on these patients at 4 months of treatment indicated a trend towards improvement of PN in patients receiving lenalidomide. Discontinuations due to PN were low in the lenalidomide cohort compared with the bortezomib cohort. Disclosures: Delforge: Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Ortho-Biotech: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Hajek:Celgene Corporation: Honoraria; Janssen-Cilag: Honoraria; Merck, Sharp, and Dohme: Honoraria. Lokhorst:Celgene Corporation: Speakers Bureau. Collins:Celgene Corporation: Employment. Rosettani:Celgene Corporation: Employment. Brandenburg:Celgene Corporation: Employment.

Abstract 42 We prospectively compared thalidomide-dexamethasone (TD) with bortezomib-thalidomide-dexamethasone (VTD) as induction therapy before, and consolidation after, double autologous stem-cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (MM). Three 21-d cycles of either VTD (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or TD were given as induction therapy. Consolidation therapy comprised two 35-d cycles of VTD (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle) or TD. 474 patients randomized to the VTD (n=236) or TD (n=238) arm were analyzed on an intention-to-treat basis for response rate, PFS and OS. Centrally reassessed CR/nCR rate was significantly higher in the VTD compared with the TD arm after all treatment phases, including induction therapy (30% vs 10%, p Disclosures: Cavo: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use of bortezomib and thalidomide as induction therapy before, and consolidation after, autologous transplantation in newly diagnosed multiple myeloma. Baccarani:NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria.

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

Abstract 1092 Background: Newly diagnosed myeloma (MM) patients who receive thalidomide-based regimens have a high risk of thromboembolic events. Preliminary studies on MM patients receiving a combination of lenalidomide (R) and dexamethasone have shown an increased incidence of thrombosis as well, with a calculated odds ratio of about 3.5 of developing thrombosis. Aims: In a prospective, multicenter phase III trial (RV-MM-PI-209) newly diagnosed patients were treated with lenalidomide and low-dose dexamethasone (Rd) induction and subsequently randomized to receive consolidation with lenalidomide + melphalan + prednisone (MPR) or high dose melphalan (MEL200). In this sub-study we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) as anticoagulant prophylaxis during Rd induction and MPR consolidation. End-points were incidence of venous thromboembolism (VTE), acute cardiovascular events, sudden death, major and minor bleeding. Methods: 402 newly diagnosed MM patients were enrolled in the randomized trial RV-MM-PI-209. Treatment schedule included four 28 day cycles of lenalidomide (25 mg days 1–21) and low-dose dexamethasone (40 mg days 1,8,15,22) (Rd) as induction. As consolidation, patients were randomized to receive six 28-day cycles of melphalan (0.18 mg/kg days 1–4), prednisone (2 mg/kg days 1–4) and lenalidomide (10 mg days 1–21) (MPR, N=202) or tandem melphalan 200 mg/m2 with stem-cell support (MEL200, N=200). All eligible patients were randomly assigned to receive LMWH (Enoxaparin 40 mg/d, N=166) or ASA (Aspirin 100 mg/d, N=176) for the duration of the induction therapy and for consolidation therapy in the MPR group; 60 patients were excluded from this sub-study because of indication for anticoagulant/antiplatelet therapy or high-risk of bleeding. Results: Patient characteristics and distribution of major risk factors were similar in the two groups. At the time of the present analysis 381 and 130 patients are evaluable during Rd induction and consolidation respectively. During the induction phase, the overall incidence of any grade 3–4 thrombotic events was 1% in the LMWH group, 2,4% in the ASA group (p=.45). VTE, mostly of the lower limbs were equally distributed in the two groups (1%; p not significant), while pulmonary embolism was observed only in the ASA group (2%; p not significant). Median time to onset of thrombotic events for patients who received LMWH or ASA were 2.1 and 1 months, respectively. No acute cardiovascular events were observed and only minor bleeding was detected in the LMWH group (1%). During consolidation no thrombotic events were observed in the MPR group, only one central venous catheter thrombosis was observed in the MEL200 group. Conclusion: The overall incidence of thrombotic events was less than 5% in all groups and confirmed the safety of low dose dexamethasone in association with Lenalidomide. No significant benefit was seen with LMWH over ASA in this patient population. LMWH and ASA are likely to be effective thromboprophylactic regimens in lenalidomide treated patients with newly diagnosed multiple myeloma. The analysis will be updated for the meeting. Disclosures: Cavallo: CELGENE: Honoraria. Guglielmelli:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Boccadoro:CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; JANSSEN-CILAG: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; JANSSEN-CILAG: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract 701 Introduction: Hairy cell leukemia (HCL) is generally responsive to intravenous Cladribine (iv2CdA). Subcutaneous Cladribine (sc2CdA) is an alternative route with 100% bioavailability. In indolent non-Hodgkin lymphomas other than HCL, at the dose of 0.7 mg/kg/cycle, efficacy of sc2CdA is similar to iv2CdA and reduction to 0.5 mg/kg/cycle determines equivalent efficacy and lower toxicity. Aims: In a national multicentre clinical trial (protocol EudraCT code: ICGHCL 2004), we prospectively evaluated toxicity and efficacy of sc2CdA given 0.1mg/kg/die for 5 (total dose 0.5 mg/kg, arm A) or for 7 consecutive days (total dose 0.7 mg/kg, arm B) as a single course in classic HCL requiring first treatment. Method: Clinical data and diagnostic samples were collected from all patients for central revision of classical HCL diagnosis (WHO criteria) and for molecular analyses at the University of Siena, prior to study entry. Early grade 3–4 toxicity was assessed on days 7 to 30 after treatment, according to the 2003 NCI/CTCAE v3 criteria and occurrence of second tumors was assessed at every subsequent follow-up. Enpoints of sc2CdA efficacy were response to treatment, treatment free interval (TFI), relapse free survival (RFS), time to second tumor (TTST) and overall survival (OS). Responses to treatment were assessed on days 60 and 180 after treatment and defined according to the 1987 Consensus criteria. Complete Remissions (CR) and Partial Remissions (PR) were rated as beneficial responses (CR/PR), while minor Responses (mR) and No Responses (NR) were rated as treatment failures (mR/NR). TFI was measured as the time elapsed from sc2CdA initiation to second treatment because of new progression or failure to sc2CdA. RFS was measured in patients with a CR/PR from treatment inititation to relapse. OS was measured from sc2CdA initiation to death for any cause. Result: of 156 patients screened centrally, 148 scored as classical HCL and entered the study. Gender (male total 116/148, 78,4%; arm A: 62/77, 80,5% vs arm B: 54/71, 76,1%), age (total: median age 52 years, range 30–83; arm A: median 56, range 30–83; arm B: median 51, range 33–82), clinical and laboratory parameters prior to treatment (including spleen, hemoglobin, platelet, leucocyte and hairy cell counts) were equally balanced in the two arms. Dose reduction was required in no patients from arm A and in 2 patients from arm B due to concurrent infection. Overall hematological toxicity was no different among the two treatment arms. Requirement of platelet transfusions (total 7/148, 4,7%; arm A: 2/77, 2,6% vs arm B: 5/71, 7%), red blood cell transfusion (total 32/148; 21,6%, arm A: 15/77, 19,5% vs arm B: 17/71, 23,9%), or G-CSF (total 102/148; 68,9%, arm A: 55/77, 71,4% vs arm B: 47/71, 66,2%) was no different among the two arms. However, a significantly higher non hematological toxicity (total 28/148; 18,9%, arm A: 9/77, 11,7% vs arm B: 19/71, 26,8%) was observed in arm B (p=.019). Non haematological toxicity was mainly represented by infections or FUO (total 25/148; 16,9%) that were significantly more frequent in arm B (arm A: 8/77, 10,4% vs arm B: 17/71, 23,9%, p=.028). Higher prevalence of toxicity resulted in a higher hospitalization rate in arm B than in arm A (total 29/148; 19,6%, arm A: 9/77, 11,7% vs arm B: 20/71, 28,2%, p=.012) and one early death was experienced because of lung aspergillosis in arm B. Onehundred-forty patients (94,6%) had a beneficial response (101 CR, 68,2%; 39 PR, 26,4%) and 8 (5,4%) failed treatment (5 mR, 3,4%; 3 NR, 2%). Responses were equivalent in the two arms, with 72/77 (93,5%) beneficial responses (49/77 CR, 63,6%; 23/77 PR, 29,9%; 4/77 mR, 5,2% and 1/77 NR, 1,3%) in arm A versus 68/71 (95,8%) beneficial responses in arm B (52/71 CR, 73,2%; 16/71 PR, 22,5%; 1/71 mR, 1,4%; 2/71 NR, 2,8%). After a median follow-up of 36 months (range 12–66), 5 year TFI, RFS, TTST and OS were 67%, 71% 87% and 94%, respectively. Causes of late death were 2 cardiac events and 3 second tumors. No differences of TFI, RFS, TTST and OS were observed in the 2 arms of treatment. Conclusion: The present data indicate that overall activity of sc2CdA is similar to iv2CdA (Cheson, 1998). Furthermore, this study indicates that sc2CdA given at 25% reduced doses (0.5 mg/kg) has equivalent activity and significantly lower toxicity than sc2CdA at standard doses (0.7 mg/kg). The reduced infection rates and hospitalization rates of sc2CdA have important pharmaco-economic implications. Disclosures: No relevant conflicts of interest to declare.

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%, P190 U/L (33% vs 9%, P10 g/dL (P=0.01). In the VTD arm, a positive correlation was observed with del(13) (P=0.006) and t(4;14) (P=0.02). Response to first ASCT with melphalan 200 mg/m2 could be evaluated in 297 pts, of whom 145 randomized to VTD and 152 to TD. Randomization to VTD was closely associated with increased CR+nCR rates (54% vs 29% with TD, P

The phase II “Bologna 2002” clinical study incorporated thalidomide-dexamethasone (thal-dex) into double ASCT with melphalan (200 mg/m2) as frontline therapy for patients with symptomatic multiple myeloma (MM) and less than 65 years of age. By study design, thal (200 mg/d) and dex (40 mg/d x 4d every month, with two added courses on the 1st and 3rd month of therapy) were administered from the outset until the second ASCT. An analysis was performed on 311 consecutive patients who entered the study from January 2002 to March 2006 and were followed for a median of 32 months. On an intention-to-treat (ITT) basis, the ≥ very good partial response (VGPR) rate increased from 29% after 4 months of primary induction therapy with thal-dex to 63% after the second ASCT. Transplantation-related mortality after first and second ASCT was 1% and 3%, respectively. Median durations of relapse-free survival (RFS) and event-free survival (EFS) were 52 and 42 months, respectively. The 5-year projected overall survival (OS) rate was 70%. A case-match comparison of 135 of these patients with an equal number of pair mates who entered the “Bologna 96” study and were randomly assigned to receive double ASCT without thal showed significant benefit from incorporation of thal into double ASCT in terms of increased ≥VGPR rate (68% vs 49%, respectively; P=0.001) and extended RFS (54% vs 32% at 5 years; P=0.005) and EFS (median: 52 vs 33 months; P=0.01). All 311 patients were screened on purified CD138+ bone marrow plasma cells for the presence at diagnosis of chromosome 13 alterations [del(13)] (47% of cases) and t(4;14) (13% of cases). In a logistic regression analysis, neither del(13) nor t(4;14) adversely influenced response (≥VGPR) to primary induction therapy with thal-dex. At the opposite, both absence of del(13) (P=0.001) and low beta2- microglobulin (beta2-m) levels (P=0.007) were significantly related to attainment of ≥VGPR after the second ASCT. In a multivariate analysis of all 311 patients, the most important variable significantly extending time to progression (TTP), EFS and OS was the absence of del(13) (P=0.001, P=0.001 and P=0.007, respectively), along with attainment of ≥VGPR after the second ASCT. OS was also significantly influenced by both beta2-m (P=0.044) and hemoglobin (Hb) concentration (P=0.05), whereas platelet count was an additional prognostic factor for TTP (P=0.025). In conclusion, in comparison with double ASCT, incorporation of thal into double ASCT as up-front therapy for MM significantly improved the response rate (≥ VGPR), RFS and EFS, without adversely affecting postrelapse OS. The presence of del(13) by FISH analysis was the most important and independent variable adversely influencing attainment of ≥ VGPR, EFS and OS following thal-dex and double ASCT.

Defibrotide has been shown to be effective in the treatment and prophylaxis of the VOD,a relatively common complication after allogeneic hematopoietic stem cell transplantation(SCT).We report our experience in 41 consecutive patients(pts) for a total of 43 SCT.The analysis,closed at day +35 after BMT,is limited to 39 SCT,since 4 pts not affected by VOD died on day +3,+11,+13 and +24,respectively.The pts(mean age 42 yrs,range 16–65) were affected by acute leukemia(14), chronic myeloid leukemia(5),lymphoma(15),multiple myeloma(2),myelodisplasia(1) and solid tumor(2).Other relevant clinical characteristics were:resistant or metastatic disease 9,previous autologous BMT 6,previous allogeneic SCT 2,previous B virus hepatitis 5,liver metastases 1 and lymphoma of the liver 1.All were transplanted from their HLA-identical sibling;the conditioning regimen was defined as reduced in 15(thiotepa,fludarabine and cyclophosphamide),while it was conventional in the other 24 SCT with use of busulphan(oral 13 and iv 11) and cyclophosphamide(VP16 added in few cases;never TBI). Thirteen received bone marrow and 26 peripheral blood as source of stem cells.No T-cell depletion was done and the GVHD prophylaxis regimen was CsA+MTX for 36 pts, CsA alone for 2 pts and FK506+MTX for 1 patient.For VOD prophylaxis no Heparin was administered,while Defibrotide was given at the dosage of 10 mg/Kg in continuous iv infusion starting on day +1 until day +21 after the SCT.Defibrotide was very well tolerated,and no hemorrhagic complications were observed.Blood coagulation significant alterations were:prolonged PT(4/39),prolonged aPTT(3/39),fibrinogen elevated(23/39,never over 800 mg/dl),low level(less than 50%) of ATIII,and/or protein C,and/or protein S(2/39).By using the VOD Baltimore criteria,only 1 case of VOD was observed at day +29 in a patient who died at day +36 with VOD,aspergillosis and CMV pneumonia.The bilirubin was more than 2 times the normal value in 20/39;US scan of the liver and Doppler,performed in 15 pts with a possibile sign of VOD,was positive only in the patient who died for VOD.We documented 29 infectious complications(14 FUO,9 gram positive bacteremias,2 pneumonia and 4 invasive aspergillosis).We observed acute GVHD in 10 pts(9 grade I–II and 1 grade III).Five pts died between +36 and +100 but none for VOD(3 for progression of their disease and 2 for aspergillosis).Since in this at risk transplanted population only 1 VOD has been observed,Defibrotide low-dose continous infusion, not associated with Heparin,seems able to play a relevant role in the VOD prophylaxis.On considering the favourable results obtained by us and Others,the absence of toxicity and the low cost of Defibrotide,we intend to continue this experience with defibrotide as VOD prophylaxis,even if we foretell a large randomized study to find better indications.

Although the evidence available associating bisphosphonates (BP) with osteonecrosis of the jaw (ONJ) is far from conclusive, the growing literature reports strongly suggest a strict relationship between them. The real frequency of this complication is unknown because of the recent observation of this condition, the bias related to retrospective studies and the wide-spread use of this supportive therapy. Aims of this research were to look for additional risk factors for developing ONJ and to determine the frequency of this event in the subgroup of patients affected by Multiple Myeloma (MM) treated with BP. We asked 49 GISL centers to participate in a retrospective multicenter study filling out a form containing several queries, including sex and age, anamnesis for smoke habit, anemia and thrombotic events, type and time of neoplasia diagnosis, treatment and neoplasia status, odonthoiatric anamnesis, type and duration of therapy with BP, microbial isolation in site of lesion, specific treatment for osteonecrosis, number of patients (pts) affected by MM treated with BP from 2002 to 2005. Fifteen centers decided to participate in the study and 12 had cases of osteonecrosis. ONJ was reported in 19 pts. Sixty % were females and the median age was 65 ys. Sixteen had MM, 1 breast cancer, 1 prostatic cancer, 1 osteoporosis steroid related. Median time from diagnosis of cancer was 54 months and median duration of treatment with BP was 34 months. Thirteen events manifested between 20 and 60 months. Of the 19 pts, 8 had received zolendronate, 2 pamidronate and 9 both drugs. None had radiotherapy on head and neck, while two received total body irradiation. In these two cases, ONJ was associated with necrosis of the pelvis. The 2 solid tumors were treated with ormonal therapy. All MM pts had received one or more line of treatment including, VAD, MP, steroids and thalidomide alone or in combination, as well as high dose melphalan, as part of autologous bone marrow transplant. ONJ involved the mandible in 14 pts, the maxilla in 3 and both in 2. Symptoms included local pain and discomfort. In 17 cases CT scan was the strumental procedure used to identifiy the lesion. In 14 pts biopsy was performed excluding localization of neoplasia in 11 cases. Microbiological evaluation of the lesion was positive in 11 pts, with 6 cases of Actynomices. In 12 patients ONJ was apparently spontaneous; in 7 occurred after dental procedures. Parodonthopaties were present in 10 pts. In 11 cases ONJ was complicated by fistula, exposed bone or abscess. BP were stopped in 17 pts. Antibiothic therapy was administered in 17 cases; 7 pts underwent hyperbaric oxygen therapy and 8 surgical debridement. Several pts improved but none were cured. Considering only the MM subgroup 16 cases of ONJ were identified among 888 pts treated with BP between 2002 and 2005, with a frequency of 1.8%. Utilizing the data collected by our retrospective study a fine statistical analysis is not applicable. However, in MM pts the frequency of steroid treatment, parodonthopaties and anemia was particularly high, respectively 100%, 56%, and 56%, supporting the idea that these are additional risk factors for developing ONJ.

Thalidomide has emerged as an active agent for the management of advanced multiple myeloma (MM) and is currently under investigation also in patients with newly diagnosed disease.[1][1] It is relatively well tolerated; more common side effects include constipation, sedation, skin rash, fatigue, and

Venous thromboembolism (VTE) has emerged as a major adverse event of primary induction therapy with thalidomide (thal) and dexamethasone (dex) for newly diagnosed multiple myeloma (MM). Aim of the present study was to investigate the relationship between thrombophilic alterations and the risk of VTE in 266 patients who received four months of therapy with thal (200 mg/d) and pulsed high-dose dex in preparation for double autologous transplantation. The rate of VTE in the whole group of patients was 11.6%. The risk of VTE was 26.3% (86.2% patient-years) among the first 19 patients who entered the study and did not received any prophylaxis against thrombosis. The corresponding value among the remaining 247 patients who received thromboprophylaxis with fixed low-dose (1.25 mg/d) warfarin during the four months of thal-dex therapy was 10.6% (35.5% patient-years) (P=0.04). Episodes of VTE occurred at a median of 53 days from the start of thal therapy and, with the exception of 3 patients, were observed after at least a partial response to thal-dex was documented. No VTE events were recorded during the first two months after the end of the induction phase. After VTE occurrence, the majority of patients went on with thal treatment plus full anticoagulation, without evidence of progression of thrombosis. One hundred and ninety patients were evaluated for the presence of thrombophilic alterations at baseline and at the end of thal-dex therapy. The prevalence of factor V Leiden (3.2%) or g20210A prothrombin (2.1%) polymorphism in patients with MM was similar to that observed in 183 healthy controls (3.3%, P= 0.81; 3.8%, P= 0.50, respectively). The relative risk of VTE for patients carrying one of these thrombophilic alterations was 20% compared with 9.4% for patients who lacked both of them (P= 0.58). Reduced protein C and S activities or acquired activated protein C resistance (aAPCR) were recorded at baseline in 11% and 7.4% of MM patients, respectively. Abnormal values at baseline normalized almost completely at the end of treatment. Carriers of aAPCR and/or of reduced levels of natural anticoagulants at baseline did not have a significantly higher risk of VTE compared with normal patients (15.2% vs 9.3%; P=0.49). In conclusion, no significant relationship was found between baseline thrombophilic alterations, including aAPCR, and the risk of thal-related VTE. Prophylaxis with fixed low-dose warfarin was associated with an apparent decrease in the rate of VTE in comparison with a subgroup of patients who did not receive any thromboprophylaxis. A prospective phase III study comparing low molecular weight heparin with fixed low-dose warfarin with aspirin is currently ongoing in Italy to evaluate the best prophylaxis against the risk of thal-related VTE for patients with newly diagnosed MM.

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

Background and Objectives. Few therapeutic options are presently available for patients with multiple myeloma (MM) who relapse after autologous or allogeneic stem cell transplantation, or for patients who are refractory to conventional chemotherapy and not eligible for salvage high-dose therapy. Thalidomide, a glutamic acid derivative with anti-angiogenic properties, has been recently proposed as an effective therapy for patients with advanced refractory disease. The aim of this study was to evaluate the activity of thalidomide in a large series of MM patients. Design and Methods. From October 1999 to January 2001, 65 patients (46 males/19 females) from 8 Italian institutions were treated with thalidomide. Twenty-six patients had relapsed after autologous stem cell transplantation, either single (n = 12) or double (n= 12); 38 patients had shown disease progression after greater than or equal to 2 lines of conventional chemotherapy, 2 patients had relapsed after allotransplant, one single patient had not received previous treatment. Sixty-one (93.8%) patients were in stage 111, median beta2 microglobulin was 2.9 mg/L, and median bone marrow plasma cell infiltration was 50%. Thalidomide was initially administered at a dose of 100 mg/day; if well tolerated, the dose was to be increased serially by 200 mg every other week to a maximum of 800 mg/day. Results. The median administered dose of thalidomide was 400 mg/day. WHO grade> II toxic effects were constipation (52%), lethargy (34%), skin rash (11%), peripheral neuropathy (14%) and leukopenia (3%). Sixty patients are presently evaluable for response; of these, 17 (28.3%) showed greater than or equal to 50% reduction in serum or urinary M protein concentration and 11 (18.3%) showed greater than or equal to 25% tumor reduction, for a total response rate averaging 46.6%. After a median of 8 months' follow-up, 15/28 patients are alive and progression-free (at 2 to 16 months), 12 patients have relapsed, and 1 patient died of pulmonary edema while still in partial remission. Among pre-treatment variables that were analyzed for their potential relationship with tumor response, only the concentration of vascular endothelial growth factor (VEGF) in the conditioned media obtained upon culture of bone marrow plasma cells was statistically significant. Plasma cells from patients who responded favorably to thalidomide secreted a significantly lower amount of VEGF than plasma cells from resistant patients (126.45 ± 165 pg/mL vs 227.11 ± 70 pg/mL, p = 0.04). Interpretation and Conclusions. These data confirm that thalidomide is active in patients with advanced relapsed/ refractory MM and represent the basis for ongoing clinical trials aimed at testing the role of this drug as front line therapy for newly diagnosed disease.