ALBERT

Description: Abstract 2873 International staging system (ISS) and cytogenetics are the main prognostic factors of Multiple Myeloma (MM) but they reflect biologic characteristics of disease without taking into account individual host features. On the contrary, clinical characteristics of single patient could be substantial as to various points of view. For instance, in elderly MM patients, novel therapies reduction or interruption due to toxicity represent the major cause of unsatisfactory outcome. Therefore, it was empirically suggested different schedule of drugs in these “frail” patients but, how the “frailty” should be assessed in every single patient, is still unsettled. Advanced age, poor performance status (PS) and comorbidities are usually applied to recognize the “frailty” but it is not well known which of them are really prominent and whether these parameters, adjusted for conventional prognostic factors, still affect final outcome. We analyzed a population of symptomatic MM diagnosed from 2007 to 2010 included in the Marche Region MM Registry, to assess the frequency of “frailty” features, such as age, PS, comorbidities, cytopenias, renal insufficiency (RI) and lytic bone lesions, and their role on the overall survival (OS) when adjusted for prognostic factors. Comorbidities were scored according to Charlson Comorbidity Index (CCI) that split patients in 4 categories according to number and type of comorbidity. Patients were treated with transplant or standard therapy according to their eligibility. Overall, 88% of patients were treated with new drug-based therapies and 12% with MP. Median age of the 266 patients analyzed was 73 years (range 38–90). Twenty-four percent of patients had IgA MM, fifty patients (23%) had ISS stage=3 and 29/166 (17.5%) had unfavourable cytogenetics. Regarding “frailty” measures, 38% of patients had 〉 75 years, 39% had PS=2–4, 34% had 1 or more comorbidities. The most frequent comorbidities were hypertension (35%), heart diseases (22%), diabetes (15%), neurological diseases (16%), COBP (8%), secondary malignancies (8%) and chronic renal failure (6%). CCI ≥1 was detected in 51%. Increasing comorbitities number and CCI were associated with increased age although 37% of patients aged less than 65 years had CCI ≥2. Moreover, 35% had at least 2 cytopenias, 76% had bone disease and 14% had RI. Fifty patients (19%) died during follow-up. OS at 3 years was 74%. Univariate analysis performed on the total population determined age 〉 65 years (p=0.065), PS=2–4 (p

Description: Abstract 2828 Poster Board II-804 Studies including thalidomide showed a rate of severe infection that can be life-threatening complication or compromise compliance to therapy ranging from 6% to 22%. Therefore, antibacterial prophylaxis has become a routine clinical practice despite its role in the new-drugs era has to be defined. We performed a post-hoc analysis of patients treated with thalidomide based combinations within controlled trials in order to assess time, type and outcome of infections. We analysed the main demographic and disease related variables to search for factors affecting onset of infections during induction and build a risk model in order to perform targeted prophylaxis. Two hundred and twenty four patients were eligible for this study. Median age was 70 years (range 31-90 years) and 141 patients (63%) had more than 65 years. Fifty three percent of patients had de novo MM whereas the remaining had received thalidomide as second or subsequent lines of therapy. ISS stage 2-3 and renal impairment were present in 156 (69%) and 38 (17%) of patients, respectively. Induction therapy consisted in the following protocols: ThaDD (160 patients: 71.5%), ThaDD-V (42 patients: 19%), VMPT (9 patients: 4%), TD (8 patients: 3.5%) and VTD (5 patients: 2%). Prophylaxis for infections was administered to 168 patients (75%) and consisted of quinolones (72%) or thrimethoprim-sulphamethoxazole (28%). Eighty six patients (38.5%) developed an infection resulting of grade 3-4 in 39 of them (17.5%) (12% grade 3, 5.5% grade 4). Probability of infection at six months was 39% although that of severe infection was 20% (18% at 4 months and just 2% from 4 to 6 months). Among the 39 patients with severe infection, 23 (59%) developed pneumonia, 9 FUO (23%), 6 bacteremia (1 septic shock) and 1 an orbital abscess. Aetiology of severe infection was recognized in 7 patients (4 Gram-negative bacteria, 1 Gram-positive bacteria, 1 CMV and 1 probable fungal infection). Eighty percent of severe infections occurred during the first 3 courses of induction therapy and only 12% during neutropenia. Fifteen percent of patients undergoing antibiotic prophylaxis developed infection vs 25% of patients who did not (p= 0.084). There were no difference between quinolones and thrimethoprim-sulphamethoxazole prophylaxis regarding incidence of infections. The majority of infections were empirically treated and cured with wide spectrum antibiotic therapy except when a specific aetiology was recognized. Only one patient died because of septic shock during neutropenia and 2 patients withdrawn from protocol because of infection. In univariate analysis monoclonal component 〉 2 g (p=0.021), platelets 〈 130.000/ml (p= 0.005), newly diagnosed MM (p=0.083) and antibiotic prophylaxis (p=0.061) were factors predicting severe infection development whereas age, sex, ECOG performance status, MM type, D-S stage, plasmacell infiltration in bone marrow, haemoglobin concentration, serum b2-microglobulin, serum albumin, ISS, serum C-Reactive Protein, serum creatinine, previous stem cell transplantation were not. Cox regression analysis selected monoclonal component 〉 2 g (p=0.015 HR= 1.8) and platelets 〈 130.000/ml (p=0.003 HR= 2.3) as covariates associated to severe infection. The 25 patients without adverse factors, the 125 with 1 and the 74 with 2 adverse factors had a probability of severe infection equal to 4%, 17% and 32 % (p= 0.023), respectively. This model remains useful apart from prophylaxis since the probability of severe infection in patients with at least 1 risk factors receiving prophylaxis is 17% vs 4% in patients without risk factors. Of note, patients developing severe infection had a significantly higher incidence of deep venous thrombosis (DVT) compared with patients who did not (20.5% vs 9%: p= 0.041). DVT occurred after a median time of 0.9 months (range 0.1-5 months; 75% within 2 months) from infection onset. In conclusion, despite antibiotic prophylaxis, patients receiving thalidomide combination therapy can develop severe infections particularly pneumonia. Wide spectrum antibiotic therapy is effective in the majority of cases since viral or fungal infections are very rare. Patients with large size of disease, represented by high MC and low platelets count, are at higher risk of severe infection that in turn significantly increase the risk of DVT. Therefore, these patients at high-risk should receive more suitable antimicrobial prophylaxis. Disclosures: Off Label Use: Thalidomide, Bortezomib and Doxil.

Description: ThaDD regimen has provided significant results in recurrent/relapsed multiple myeloma (MM) patients (Offidani et al, 2006). In order to further improve those results without significantly increasing toxicity, we decided to include Velcade, synergic as per activity but not toxicity with the other drugs of ThaDD regimen. ThaDD-V was scheduled as follows: Thalidomide 100 mg/day, pegylated liposomal Doxorubicin 30 mg/sm iv days 4; Dexamethasone 20 mg days 1–2, 4–5, 8–9, 11–12 and Velcade 1.3 mg/sm iv days 1, 4, 8, 11 every 28 days (induction therapy). Patients received bortezomib for alternate cycles as following: 1 mg/sm day 1, 8, 15 and dexamethasone 20 mg days 1–2, 8–9, 15–16 and thalidomide 100 mg/day and dexamethasone 40 mg/day for 4 days monthly for a total of six cycles as consolidation therapy. Then patients received thalidomide 100 mg/day until relapse (maintenance therapy). Actually 20 patients (7 M, 13 F; median age 62.5 yrs, range 31–75) are assessable for response and toxicity. Five pts (25%) showed WHO performance status (PS) 〉 1, 9 pts (45%) presented refractory disease, 8 pts (40%) were priorily administered ≥ 2 lines of a treatment and 14 patients (70%) were submitted to one previous autologous stem cell procedure. Seven patients (35%) had extramedullary disease and 7 had unfavourable cytogenetics. Twelve patients scored an ISS ≥ 2 and 11 (55%) were in first remission for ≤ 12 months median duration. No patients were previously treated with Velcade, whereas six patients had received short-term Thalidomide treatment. Response was assessed according to IMVG uniform response criteria. Seventeen of 20 patients responded after at least one chemotherapy cycle reporting 5 (25%) sCR, 3 CR (15%), 8 VGPR (40%) and 1 stable disease. Three patients (15%) had extramedullary progressive disease. In a median follow-up of 12 months, 2 (10%) patients progressed and 1 (5%) died from cardiac infarction. Time to progression and overall survival were 73% and 95% at 12 months. We observed 4 grade 3 thrombocytopenia, 2 grade 3 DVT, 1 grade 3 diarrhoea, 1 grade 3 asthenia, 1 grade 4 infection and 1 grade 3 dermatological toxicity. Six patients developed grade 2 peripheral neuropathy and other three grade 3. In conclusion, ThaDD-V is extremely active in advanced MM patients as demonstrated by the elevated precentage of high quality remission. Nevertheless, patients are at substantial risk of developing neurotoxicity so the protocol was amended as per Velcade dose intensity and Thalidomide dose.

Description: Maintenance therapy with Thalidomide in MM offer controversial results. De novo or relapsing MM patients presenting at least a minor response after ThaDD were randomized to receive Interferon 3 MU x 3/week or thalidomide 100 mg /d. Both groups were given also Dexamethasone 20 mg/d x 4 days every month. Actually, we have randomized 50 patients in both treatment arms. The two groups were matched for main prognostic factors and response. During maintenance, both the ID and TD regimens improved response obtained by induction in only 10% and 11% of patients, respectively (p=0.832). After a median 2-years maintenance follow-up for both arms, 30 ID patients (60%) relapsed vs 17 (33%) TD ones (p=0.009). Time-to-progression (TTP) was significantly higher in the TD group vs the ID one (p= 0.024). So that TTP amounted to 23% in the ID group vs the 44% in the TD one. In addition, 3-years overall survival (OS) was significantly better in the TD arm with a value of 67% vs 46% of ID (p = 0.030). Both treatment arms were overall fairly well tolerated: fever, anorexia, weight loss, fatigue, liver and heart function abnormalities and hematologic toxicities were significantly more frequent in the ID cohort whereas neurotoxicity was somewhat more frequent in the TD one. This turned into a rate of therapy dropouts rate significantly higher in the ID group than in the TD one (26% vs 8%; p=0.017). Anyway, estimated risk for treatment interruption due to side effects in a 3-years period with thalidomide was only 21% vs 44% for interferon (p =0.014). We concluded that, in MM patients responding to standard induction therapy, low-dose Thalidomide maintenance therapy is feasible even in the long run and offers a significantly longer control over residual disease when compared to standard maintenance regimen.

Description: Abstract 4769 From 1980 to 2005 in our institution we've diagnosed and treated 361 patients (pts) affected by Hodgkin's disease. At the moment of diagnosis the median age of the patients was 29 years (range 13-69).About 72% of patients were in the stage I-II and 28% were in the stage III-IV. More than 54% of all patients received ABVD, 17% received MOOP, 10% MOOP/ABVD, 3% VBM and 1% received Stanford V scheme. Over 70% of all patients received radiotherapy (RT) with median dose of 4500 cGy (range 1000-16210). Over 94% of all patients obtained a Complete remission, however 11% relapsed. 130 patients among 361 are at this moment evaluable for late effects of chemo-radiotherapy.26 pts were treated in the period 1980-84 (25%) ; 6 pts treated 1985-89 (4,6%);21 pts treated in 1990-94 (16,1%); 24 pts treated in 1995-99 (19%) and 35 pts in the period 2000-2005 (27%). 50 pts among 130 (38,5%) present late effects related to the therapy. 24 pts (48%) present heart disease: 13 pts (40%) Valvulopathy,8 pts (25%) Ischemic heart disease, 7 pts (21%) Congestive heart failure, 4 pts (14%) Pericardic disease. Therapies of these patients were performed : In 1980-89 (11 pts), 6 pts (25%) received MOOP + RT,2 pts (8,3%) received M/A and 3 pts only RT. In 1990-99 (7 pts), 3 pts(12,5%) received ABVD +RT, 2 pts(8,3%) received MA+RT, 1 pt(4,1%) received ABVD and 1 pt(4,1%) received M/A. In 2000-05 (6 pts), 2 pts (8,3%) received ABVD+RT and 4pts(16,6%) received only ABVD. 18 pts present Endocrinological-disease, in all cases, represented by hypothyroidism; 16 pts among 18 had done Chemoteraphy and Radiotheraphy, while 2 pts received only Chemotheraphy. Besides 8 pts show both endocrinological and cardiological disease; in these cases 3 pts (37,5) had done ABVD+RT, 4 pts (50%) MOOP+RT and 1 patient (12,5%) only RT. Furthermore 26/130 (20%) developed a second neoplasm. Conclusions In our population 38% of patients had developed secondary late effects and we assess that about 15% of our Hodgkin's population die for a secondary late effect of therapies Although there are many variables for the development of a late effect we think that this analysis could lead to try to reduce the late toxicities of treatments. Disclosures: Offidani: Celgene: Honoraria; Janssen Cilag: Honoraria.

Description: New drugs such as thalidomide, bortezomib and lenalidomide have expanded the therapeutic options for MM while improving outcome in both young and elderly patients. However, the best novel agents sequence in the therapeutic strategy for MM is still not definitely delineated as relapsed MM right after first line thalidomide therapy seems to be more resistant jeopardizing final outcome as per overall survival while still making questionable when to administer it, either at the beginning or later during the course of the disease. We analyzed 72 relapsed MM patients who were enrolled in two salvage study protocols which included bortezomib, dexamethasone and chemotherapy (Offidani et al, ASH 2007 and EHA 2008) and who had been treated with thalidomide first (18 patients) or subsequently (30 patients) or not treated at all with thalidomide (24 patients). We compared these three groups of patients in terms of response rate, post-relapse PFS and post-relapse OS with the aim to assess the role of previous administration of thalidomide on final outcome in this patient population. Median age for the 72 patients was 65 years (range 31–82); ISS stage 2–3 assessed in 51% of patients and unfavourable cytogenetics in 42%. Thirty four patients had been rescued in first relapse, 19 in second and 19 in third or subsequent relapse. Median disease history was 34 months (range 8–173). Forty four patients relapsed after high-dose therapy and autologous stem cell transplantation. The 48 patients were previously treated with thalidomide a median time of 8 months (range 4–48 months). VGPR or better response rate in the groups of patients treated with thalidomide in first line, second or subsequent line or never treated with thalidomide were 44%, 42% (p=0.795) and 79% (p=0.003; p=0.002), respectively.. Multivariate stepwise regression analysis selected only previous thalidomide treatment (OR=1.9; 95%CI=1.5–2.4; p=0.024) as factors affecting response whereas age, previous therapy lines, previous remission duration, previous transplant, previous disease history, sCRP, ISS stage and cytogenetics were not significantly associated to response. In the same groups post-relapse PFS was 9 months, 14 months (p=0.308) and not reached (p=0.018; p=0.055) while post-relapse 2 years OS was 51%, 50% (p=0.564) and 72% (p=0.074; p=0.135). Cox regression analysis showed that the presence of ISS 2–3 (p=0.010), previous thalidomide administration (p=0.052), and response 〈 VGPR (p

Description: Previously we reported the outcome of 50 patients treated with an induction ThaDD regimen followed by a randomized maintenance therapy with a-Interferon or thalidomide and low-dose dexamethasone. At present, 88 patients with newly diagnosed MM have been enrolled in the ThaDD protocol. Here we present the updated results of the first 50 enrolled patients after a 42 months median follow-up (range 27–60). Baseline characteristics of the 50 patients were previously reported. Briefly, median age 72 years (range 65–78; 14% ≥ 75 years), more than three quarter of patients scored ISS 2–3, 60% presented abnormal serum levels of C-reactive protein (sC-RP) and 24% had unfavourable cytogenetics. Post-randomization best response included 34% CR, 14% nCR, 14% VGPR, 28% PR and 6% MR. One patient was diagnosed with progressive disease and two (4%) died early before response assessment. Median and 3-years TTP was 32 months and 40%, respectively. Median and 3-years PPF was 24 months and 38%, respectively. Factors negatively affecting PFS in univariate analysis were age 〉 70 years (p=0.054), abnormal sC-RP level (p=0.023), randomization to Interferon (p=0.046) and response to induction 〈 VGPR (p=0.031) whereas high ISS score, high b2-microglobulin level and unfavourable cytogenetics did not. Multivariate stepwise analysis select abnormal sC-RP (p=0.021; HR=4.1) and response 〈 VGPR (p=0.022; HR=3.8) as adverse features for PFS. Subgroups analysis shows that thalidomide maintenance therapy offered a significantly better PFS (42.5 vs 23.5 months; p=0.015) particularly in non VGPR patients; moreover, consolidation with high-dose therapy and autologous stem cells transplant seems to overcome the adverse impact of abnormal sC-RP albeit it did not significantly prolong PFS in the whole transplanted population vs no-transplant population. First line salvage therapy of relapsed patients was bortezomib-chemotherapy based therapy (Offidani et al, EHA 2008). Three-years OS was 64% and it seems not adversely affected by long-term thalidomide maintenance therapy since response rate and post-relapse PFS were similar between in those patients randomized for Interferon or thalidomide. ThaDD was fairly well tolerated but DVT/PE occurred in 7 patients undergoing prophylaxis with fixed dose warfarin and severe infection in 20% (7% after antibiotic prophylaxis). Grade 3–4 neutropenia occurred in 5 patients whereas no patients presented 〉 grade 2 thrombocytopenia. Only 2 patients dropped out due to toxicity (1 EP, 1 severe infection). During thalidomide maintenance severe peripheral neuropathy was observed in 2 patients and 2 other patients died for myocardial infarction. In conclusion, patients treated with ThaDD showed similar TTP, PFS, OS and non-hematological toxicity but less hematological toxicity and better compliance compared to that reported in patients treated with MPT (Palumbo et al, Blood 2008; Facon et al, Lancet 2006) or VMP (Mateos et al, Haematologica 2008; San Miguel et al, EHA 2008). Patients with normal sC-RP level and achieving at least VGPR after ThaDD gained a very long PFS. However, even patients with abnormal sC-RP level or who didn’t achieve VGPR could have a long-term PFS if transplanted or maintained with thalidomide after induction, respectively. Outcome of salvage therapy with bortezomib, dexamethasone and chemotherapy seems to be not affected by time on thalidomide treatment.

Description: Multiple myeloma represents a typical disease of old age as reported by recent epidemiological data showing that the incidence of MM in persons aged above 75 years is more than 30%. Very elderly MM patients remain very difficult to treat since they more likely have comorbid medical conditions and a poor performance status, limiting the chance of chemotherapy administration. Moreover, this populations is often underrepresented in clinical trials and few studies are specifically designed for patients of old age. Besides these problems, it has to be underlined that not even the introduction of new agents (thalidomide, lenalidomide, bortezomib) has been able to improve survival in patients older than 70 years if compared with younger ones. The aim to this retrospecive study was to assess the safety and efficacy of ThaDD regimen (thalidomide 100 mg/day continously, pegylated liposomal doxorubicin 40 mg/m2 on day 1 for 6 28-day cycles, dexamethasone 40 mg on days 1–4 and 9–12) in 27 newly diagnosed MM patients older than 75 years. In this group of patients median age was 77 years (range 75–91), performance status was poor in one third, 78% had ISS score ≥ 2, 37.5% showed unfavourable cytogenetics abnormalities and 30% impaired renal function. At least a PR and a VGPR were achieved in 85.5% and 52% of patients, respectively, with 15% of them obtaining a CR. After a median follow-up of 25 months (range 7–58), median PFS was 25 months. Two-year PFS and OS resulted 50% and 75%, respectively. More frequent grade 3–4 non hematological side effects were peripheral neuropathy (15%) and constipation (11%). A severe neutropenia was observed only in 4% of patients and in 2 patients (7.5%) occurred a febrile episode requiring antibiotic therapy. On thromboprophylaxis with fixed-dose warfarin, 5 patients (18.5%) developed a deep venous thrombosis and one patients with carotid arteriopathy experienced acute stroke. Two patients died early during treatment, because of acute liver failure and heart attack, respectively. No significant differences in term of toxicity were found between this group of patients and patients younger than 75 years receiving the same regimen although in these latter vascular events were twice as much and early mortality rate higher. Overall, the compliance with therapy was satisfactory and only one patient stopped treatment due to the occurrence of atrial fibrillation and deep venous thrombosis. Pegylated liposomal doxorubicin administration was delayed in one patient who developed fever and mucositis whereas in another patient dexamethasone dose was reduced because of miopathy. Thalidomide discontinuation was necessary in 2 patients due to severe neuropathy and pulmonary embolism, respectively. Our study demonstrate that also MM patients older than 75 are able to derive benefit and to tolerate treatments used for younger patients although in very elderly vascular events seem to be more frequent and requiring maximal care. In patients with poorer performance status drugs adjusted-dose is probably needed to reduce early mortality.

Description: Abstract 3020 Background. In patients with newly diagnosed MM, three/four-drug combinations seem to be more effective compared with two-drug associations in terms of both rate and duration of remission. Moreover, there is an emergent body of evidences that consolidation/maintenance therapy improves quality of response and remission duration. However, the impact of these strategies in relapsed/refractory MM (r-rMM) are still unknown. Methods. This is a multicenter, phase II study including patients with r-rMM having measurable disease, no more than 4 prior lines of therapy, adequate performance status, cardiac and liver function. As induction therapy patients received 6 28-day cycles of oral thalidomide 100 mg/day continuously at bedtime, oral dexamethasone 20 mg on day 1–2, 4–5, 8–9, 11–12, pegylated Liposomal Doxorubicin (pLD) 30 mg/m2 iv on day 4 and bortezomib 1.3 mg/m2 iv on day 1, 4, 8, 11 (ThaDD-V). As consolidation patients underwent 6 28-day cycles of rotating bortezomib 1.3 mg/m2 iv on day 1, 4, 8, 11 plus oral dexamethasone 20 mg on day 1–2, 4–5, 8–9 (3 courses) or thalidomide 100 mg/day continuously at bedtime plus oral dexamethasone 20 mg on day 1–4 (3 courses). Patients eligible and having suitable stem cell storage underwent ASCT instead of standard consolidation at the discretion of attending physician. Maintenance therapy included thalidomide 100 mg/day until relapse or intolerable toxicity. Since in the first 20 patients we recognized an excess of peripheral neuropathy, protocol was amended as follow: bortezomib 1.3 mg/m2 on day 1, 4, 11 and thalidomide 50 mg/day in all therapeutic phases. The primary end-points of this study were best response and toxicity of the planned therapy. Results. Forty-six patients were enrolled. Median age was 63.5 years (range 31–80 years) and the median number of prior regimens was 1 (range 1–4). Twenty-four patients (52%) had undergone autologous stem cell transplantation, 30 (65%) had received anthracyclines, 27 (59%) thalidomide, 8 (17.5%) bortezomib and 16 (35%) were refractory to the last regimen. After induction 16 patients (34.5%) achieved CR (6=13% sCR), 15 (32.5%) VGPR and 4 (8.5%) PR with a ORR of 76.5%. Seven patients (15%) progressed. Out of 46 patients undergone induction, 26 (20 standard, 6 ASCT) received consolidation therapy since 1 patients died during induction, 8 had progressive disease, 1 had second neoplasm, 7 had severe toxicities and 3 undergone allogeneic stem cell transplantation. Excluding 6 patients who have obtained sCR before, 5 (25%) out of 20 patients had further improvement in response. Therefore, best response after induction and consolidation were: 25 CR (54%; 8 sCR=17.5%), 16 VGPR (34.5%) and 2 PR (4.5%). Maintenance therapy did not further improve response. Patients receiving ≤ 2 prior regimens had a CR rate significantly higher than those heavily treated (41% vs 0%; p= 0.010) whereas prior ASCT, thalidomide or bortezomib, refractory disease and bortezomib dose-intensity did not affect quality of response. After a median follow-up of 31 months (range 12–53), 28 patients relapsed and 20 died. Median TTP was 18.5 months, median PFS was 17.5 months and median survival was 40 months. Median TTP of patients achieving PR-VGPR was 16 months (3 years= 10%) whereas in those obtaining CR it was 32.5 months (3 years= 45%; p=0.032) vs not reached (3 years= 85%) in patients achieving sCR (p=0.003). Main toxicity was peripheral neuropathy (PN). Indeed, in the first 20 patients we observed 6 (30%) grade 2 and 3 (15%) grade 3 PN. After amendment, grade 2 and 3 PN occurred in 3 (11.5%) and 2 patients (7.5%), respectively. DVT occurred in 2 patients (4.5%) and severe infection in 7 (15%). Grade 3–4 neutropenia, anemia and thrombocytopenia occurred in 4 (8.5%), 2 (4%) and 7 patients (15%), respectively. Finally, only one patients died of myocardial infarction during induction. During consolidation therapy other 2 patients developed grade 3 peripheral neuropathy. During maintenance with thalidomide no patients developed severe neuropathy requiring discontinuation. Conclusions. Multi-drug combination namely ThaDD-V as induction followed by consolidation-maintenance therapy seems to be very effective in patients with r-rMM provided that this procedure is used early on relapse when very deep responses are still possible. A reduced dose-intensity of bortezomib significantly decreases PN without jeopardizing outcome. Disclosures: Offidani: Celcene, Janssen Cilag: Honoraria. Polloni:Celgene: Honoraria. Corvatta:Celgene: Honoraria. Gentili:Celgene: Honoraria. Brunori:Celgene, Janssen-Cilag: Honoraria. Catarini:Cerlgene, Janssen-Cilag: Honoraria. Malerba:celgene, Janssen-Cilag: Honoraria. Leoni:Celgene, Janssen-Cilag: Honoraria.

Description: Abstract 3019 Background: Panobinostat (LBH-589) is a pan-deacetilase inhibitor that targets histone proteins increasing tumor suppressor gene activities leading to cell-cycle and differentiation arrest besides to target non-histone proteins such as HSP90, aggressomes, p53, HIF-1a, and a-tubulin somehow promoting cell death. Panobinostat, combined with steroids and/or immunomodulatory drugs, demonstrated additive/synergistic activity in Multiple Myeloma (MM) and ability to overcome previous chemoresistance. Several combination studies with Panobinostat plus novel drugs are now ongoing in MM. Methods: This is a multicenter, open-label, phase I-II study exploring the combination of a standard therapy such as MPT (Melphalan 0.18 mg/kg per os for 4 days, Prednisone 1.5 mg/kg per os for 4 days, Thalidomide 50 mg/day continuously) with Panobinostat 15 mg p.o. thrice weekly for 3 weeks in a 28-day cycle to assess safety profile and activity of this combination in patients with relapsed/refractory MM having adequate performance status and haematological, cardiac, liver and neurological functions. The study was designed according to the Briant and Day method that plans a “dose-escalation phase” to determine both the MTD and the activity of the study drug and an “expansion-phase” in which the MTD of the study drug is used to further assess its safety and efficacy. Despite in the first phase of this study 19 patients were planned according to the study design, protocol was amended after 13 patients had been enrolled since more than 50% grade 3–4 toxicity occurred although response criteria were met. Therefore, Panobinostat was reduced to 10 mg p.o. thrice weekly for 3 weeks in a 28-day cycle whereas the dose of drugs of the MPT combination was not modified. Toxicity and response were assessed according to CTC version 4 and IMWG criteria, respectively. Results: As of February 2010, 24 patients were enrolled in this study. Median age was 71.5 years (range 40–81 years) and 12 patients (50%) had ISS 2–3 score. Patients had received a median of 2 prior therapies (range 1–6) and 5 (21%) three or more prior lines of therapy. Sixteen (73%), 13 (54%), 18 (75%), 11 (46%) and 9 (37.5%) patients had been previously treated with ASCT, thalidomide, bortezomib, lenalidomide and all 3 new-drugs, respectively. Seven patients (29%) were refractory to the last therapy. Twelve patients (50%) had a disease history longer than 5 years. In the first 13 patients treated with Panobinostat 15 mg, grade 3–4 thrombocytopenia and neutropenia occurred in 6 (46%) and 9 patients (69%), respectively. Moreover, 4 patients (31%) developed non-hematological adverse events such as fatigue, constipation, infection and arrythmia. In the group of 11 patients treated with Panobinostat 10 mg, grade 3–4 thrombocytopenia decreased to 18% (2 patients) but neutropenia was still high (8 patients: 72.5%). Three patients (27%) had grade 3–4 non-hematological toxicity (one fatigue and two constipation). No patients had QTcF prolongation or severe neuropathy. Dose adjustment was necessary in 9 patients (37.5%, all due to hematological toxicity) while 6 patients (25%) interrupted the protocol because of side effects (5 due to no resolution of grade 3–4 hematological toxicity within 4 weeks and one due to atrial fibrillation). One patient (4%) died on study due to sepsis during prolonged neutropenia. Response ≥ PR were observed in 12 patients (50%) including 4 VGPR and 8 PR. Additionally, 2 patients had MR and 8 SD. Only 2 patients progressed during treatment. There was no difference between the two cohorts of patients (Panobinostat 15 mg and Panobinostat 10 mg) in terms of response ≥ PR (54% vs 45.5%) or disease progression (7.5% vs 9%). Notably, response was obtained also in 2/7 patients (28%) who progressed during bortezomib or IMIDs. Conclusions: This study suggests that MPT-Panobinostat combination has an encouraging anti-myeloma activity since responses were still seen in patients with advanced stage or resistant to new drugs diseases. Different schedules of Panobinostat/melphalan should be explored to reduce haematological toxicity. Disclosures: Offidani: Celgene: Honoraria. Off Label Use: Panobinostat in relapsed/refractory multiple myeloma. Cavallo:Celgene: Honoraria. Polloni:Celgene: Honoraria. Ballanti:Celgene: Honoraria. Catarini:Celgene: Honoraria. Alesiani:Celgene: Honoraria. Corvatta:Celgene: Honoraria. Gentili:Celgene: Honoraria. Boccadoro:Celgene: Honoraria, Research Funding. Leoni:Celgene: Honoraria. Palumbo:Celgene: Honoraria, Research Funding.