ALBERT

Description: Acute lymphoblastic leukemia (ALL) represents a rare malignancy in the elderly and few authors have specifically focused on the treatment of ALL in this setting. We recently published the results of a prospective phase II study comprising an induction therapy with vincristine, Daunoxome, cyclophosphamide and prednisone (VDXD) given to 15 patients aged ≥ 60 years. Here, we updated the results after enrolling 17 patients treated from 1999 to 2002 (median age 69 years, range 61–79) and we compared these with the results obtained in 17 elderly patients treated according to the GIMEMA ALL 0288 protocol from 1994 to 1998 (median age 70, range 61–76). Most of patients in both groups had B-lineage ALL and an initial WBC count less than 30 x 109/L. The most frequent karyotypic abnormality resulted the Ph which was detected in 4 (23%) and in 3 patients (17%) treated with 0288 and VDXD, respectively. BCR-ABL translocation was present in 45 % of patients treated with VDXD. Comorbidities were documented in 11 (65 %) patients treated with VDXD compared with 9 (58%) receiving 0288 regimen. With VDXD combination elderly ALL had a higher CR rate than with 0288 protocol (76.5% vs 41%; p=0.037) likely due to both lower induction mortality (17.5% vs 35%; p=0.028) and less resistant disease (6% vs 24%; p=0.025). Infectious complications rate was similar (64% vs 53%) but they were the primary cause of death in 2 and 5 patients receiving VDXD and 0288, respectively. Non-hematological side effects were comparable. Median DFS was similar and resulted 18 months and 20 months with 0288 and VDXD treatment, respectively. Median EFS was 3.9 and 12.8 months, respectively (p = 0.0486). Particularly, 1-year EFS resulted 35% in patients receiving 0288 treatment compared with 53% in those given VDXD. Median OS was 4.5 an 21 months in the first and in the latter group of patients (p = 0.0239) with a two-year OS of 29% in 0288 and 38% in VDXD group. Our results are encouraging and show that the administration of high-dose daunorubicin as liposomal compound in elderly ALL patients is not only feasible but also able to improve CR rate, EFS and OS without increase in toxicity.

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.

Description: Despite the improvements in the treatment of MM patients, they ultimately progress and die of their disease since all attempts to control residual disease with a maintenance therapy have substantially failed in providing significant results. Nevertheless, maintenance therapy may still be an appealing approach. We treated 120 de novo or relapsed/refractory MM patients with Thalidomide, Dexametasone and peghilated liposomal Doxorubicin (ThaDD) as induction treatment of de novo or relapsed/refractory MM. All patients achieving at least minor response were randomized to receive Thalidomide 100 mg continuously or IFN-α 3 MU three times per week subcutaneously until the occurrence of relapse or major toxicities. Both drugs were combined with oral 20 mg Dexamethasone for 4 days monthly. In the original protocol an interim analysis was planned after a median follow-up of two years in order to assess a unacceptable imbalance between the two treatment arms leading to a premature interruption of protocol. At this moment, 74 patients are evaluable for maintenance therapy, 36 in the Thal-dex arm and 38 in the IFN-dex arm. The two groups of patients were matched on the basis of the main prognostic factors as age, serum β2-microglobulin, serum albumin, ISS score, CRP, cytogenetics and response to therapy. IFN-dex and Thal-dex improved response in 13% and 17% of patients, respectively (p=0.532) whereas rate of progression (58% vs 36%; p=0.0061) and mortality (42% vs 19.5%; p=0.035) were significantly higher in the IFN-dex arm. After a median 24 months follow-up, median TTP was 21 months and 2 years TTP was 45% in the IFN-dex arm vs Thal-dex arm whereas median was not reached and 2 years TTP was 59% (p=0.0139). A clear better OS trend was observed in the Thal-dex arm when compared with IFN-dex arm (2-yrs OS 84% vs 71%; p=0.0821). Multivariate analysis found serum CRP ≤ 3 mg/l, not unfavourable cytogenetics, response to induction ≥ VGPR and maintenance with Thal-dex significantly associated with better TTP. Both treatment arms were overall well tolerated: fever, anorexia, weight loss, fatigue, liver and heart function abnormalities and hematologic toxicities were significantly more frequent in the IFN-dex arm whereas neurotocity (somnolence, constipation and peripheral neurophaty) were somewhat more frequent in the Thal-dex arm. This turned into a rate of therapy reduction and interruption significantly higher in the IFN-dex arm than in the Thal-dex one (23% vs 5%; p=0.0231). In conclusion, our data show that in MM patients the combination Thal-dex administered as maintenance therapy after thalidomide, dexamethasone and chemotherapy combination, although it does not significantly improve the quality of response obtained after induction therapy, is significantly better in controlling residual disease than the IFN-dex combination which, on the other hand, leads more frequently either to systemic side effects or organ toxicity.

Description: Introduction: Bendamustine, a bifunctional alkylating agent, exerts a mechanism of action different from that of other conventional alkylators despite it remains mostly unknown. In patients with newly diagnosed or relapsed-refractory MM bendamustine has proven to be active either as monotherapy or in combination with new drugs, particularly bortezomib and immunomodulatory agents. Methods: The preliminary results of this prospective, phase II study conducted in 22 Italian centres are recently published (Blood Cancer J. 2013, 3: e162). Here we present the conclusive results of the combination Bendamustine (70 mg/m2 days 1, 8), Bortezomib (1.3 mg/ m2 days 1, 4, 8, 11) and Dexamethasone (20 mg days 1-2, 4-5, 8-9, 11-12) (BVD) administered every 4 weeks in patients with relapsed-refractory MM of any age, with adequate cardiac, liver and hematological function, not refractory to bortezomib and treated with no more than four previous lines of therapy. The primary endpoint of this study was achievement of a response at least PR, as to IMWG criteria, after four cycles of BVD. Patients achieving a response less than a PR were taken off-study. Patients obtaining at least a PR received two additional treatment cycles followed by a 12-months consolidation phase with cycles repeated every 2 months. Therefore, patients with a PR after the induction phase could receive up to 18 months of treatment and up to 12 cycles of BVD. Results: 75 patients were included in the study. Median age was 68 years (range 41-85 years), 26.5% had ISS stage 3, 19% IgA myeloma and 9% renal failure. Eight of 36 evaluable patients (22%) had high-risk cytogenetics. Patients had received a median of one prior line of therapy (range 1-4). All patients had received prior treatment with new drugs, such as thalidomide (57%), lenalidomide (54.5%), bortezomib (46.5%) or both (20%). Twenty-four patients (32%) were refractory to IMIDs. Best response rate was 75%, including 14 CRs (20%), 22 VGPRs (24%) and 27 PRs (31%). Five patients (6.5%) died early. Only prior treatment with bortezomib significantly reduced the response rate ≥ PR (48.5% vs 80%; P = 0.004). At a median follow-up of 27 months (range 18-38), 45 patients had progressed and 43 had died. Median TTP and PFS were 17 and 12.5 months, respectively while median OS was 24 months (40% at 3 years). After longer follow-up, prior therapy with bortezomib plus lenalidomide was confirmed as the only factor that significantly reduced TTP (9 vs 19 months; HR = 2.7; 95% CI = 1.3-5.8; P = 0.009), PFS (9 vs 15 months; HR = 2.1; 95% CI = 1.2-3.8; P = 0.020) and OS (17 vs 32 months; HR = 2.1; 95% CI = 1.2-3.9; P = 0.043). Grade 3-4 adverse events occurred in 55% of patients leading to therapy reduction in 24% and to protocol discontinuation in 11% of patients. The most frequent severe adverse events were thrombocytopenia (28%), neutropenia (20%), infections (12%), peripheral neuropathy (9%), gastrointestinal (5%) and cardiovascular events (4%). Compared with younger, patients aged 〉 70 years had a significantly higher incidence of grade 3-4 side effects particularly thrombocytopenia and infections with, consequently, a higher rate of therapy reduction and discontinuation. Moreover, 4/5 early deaths occurred in patients aged more than 70 years. Conclusions: BVD combination is an effective and well tolerated regimen in relapsed-refractory MM. Data suggest that the optimal target of BVD maybe patients younger than 70 years who has not previously received both bortezomib and lenalidomide. Disclosures Offidani: Mundipharma, Janssen: Honoraria. Off Label Use: Bendamustine. Corvatta:Janssen: Honoraria. Ballanti:Janssen: Honoraria. Brunori:Janssen: Honoraria.

Description: Abstract 5003 Multiple myeloma (MM) is a disease typically characterized by repeated relapse that needs several new-drugs throughout its clinical course. Therefore, increasing knowledge of the pathways involved in the pathophysiology of MM will contribute to identified new therapeutic strategies. Specific signaling pathways as: nuclear factor kappa B (NFkB), farnelsyl-transferase (FTI), mitogenen-activated protein kinase (MAPK), proteosoma and others have been found to be disregulated in MM patients and cell lines. These findings have allowed the design of specific inhibitors that have been assessed in preclinical and clinical studies. Recent data have highlighted the contribute of ion channels (K+, Cl−, Na+ and Ca2+) in the regulation of cell proliferation, chemo-resistance, migration and invasion. Transient Receptor Potential Vanilloid type-2 (TRPV2) is a cation channel, member of the TRPV family, and its expression in human cancer cells and tissues has been reported for gliomas, prostate, bladder and pancreas, while no data were available in MM or in other hematological malignancies. TRPV2 expression has been found to influence cancer cell responses to chemo-therapeutic drugs as well as proliferation, migration and apoptosis, in part by increasing intracellular Ca2+ influx and/or by regulating specific signal pathways, like MAPK associated pathways. TRPV2 responds to noxious heat with an activation threshold of 〉52°C as well as to changes in osmolarity and membrane stretch; in addition, TRPV2 is activated by agonists such as 2-aminoethoxydiphenyl borate, as well as cannabinoids. The aim of this study was, firstly, to evaluate if TRPV2 was expressed in three human MM cell lines established models (RPMI, SKO-007, U266). Secondly we investigated on the role of TRPV2 activation in regulating the proteosoma inhibitor Bortezomib activity, in MM cell lines. By Real-Time PCR analysis we demonstrated that TRPV2 gene was expressed, with comparable relative levels, in the MM cell lines studied, and similar results were obtained at protein levels by Western blot analysis. Moreover, by immunofluorescence and FACS analysis we found that the percentage of TRPV2+ cells was 11% in RPMI, 3% in U266 and 2.6% in SKO-007. These data indicate that TRPV2 was expressed at low levels in MM cell lines. Since lost of TRPV2 expression was found to be associated with higher cell proliferation rate, in other tumor cell lines, and increasing of TRPV2 transcription and/or activity by specific agonists induced cell death and anti-proliferative effects, we evaluated the biological effects of TRPV2 activation in MM cell lines by MTT assay. The results showed that, after three incubation days, TRPV2 activation induced a decrease of cell viability of 70% in RPMI, 60% in U266 and 55% in SKO-007, compared to control. To evaluate if the reduced cell viability was dependent by an anti-proliferative and/or apoptotic process, the three cell lines treated with the TRPV2 agonist were analyzed by 5-bromo-2-deoxyuridine (BrdU) incorporation assay for proliferation and by Annexin-V apoptosis assays. Data shown a decrease of BrdU+ cells in TRPV2 agonist treated cells (40% in RPMI, 30% in U266 and 28% in SKO-007) compared to control, while no significant differences were observed by Annexin-V analysis. Moreover, to evaluate a putative role of TRPV2 in influencing Bortezomib cytotoxicity, RPMI, SKO-007 and U266, were co-treated with the TRPV2 agonist in combination or not with Bortezomib, for three days. By a dose-response MTT analysis we determined that TRPV2 activation reduced MM cell lines viability more than 40% in RPMI, 20 % in U266 and 15% in SKO-007, compared to Bortezomib (5 ng/ml) alone. Summarizing, these preliminary data demonstrated that the TRPV2 cation channel was expressed in human MM cell lines and that activation of TRPV2 could play a role in increasing Bortezomib cytotoxicity, by inhibiting cell proliferation rather than increasing apoptosis of MM cells. These data may open new perspectives in combination therapy, albeit the molecular mechanisms undergone TRPV2 activation needs to be clarified. Disclosures: No relevant conflicts of interest to declare.

Description: Bendamustine, a bi-functional alkylating agent comprising a purine-like benzimidazole ring an a nitrogen mustard group, exerts a peculiar mechanism of action if compared to most conventional alkylators and this may partially explain its effectiveness in alkylator-resistant cells. In patients with MM several studies demonstrated the efficacy and tolerability of bendamustine as monotherapy or in combination with new drugs, particularly bortezomib that was found to enhance the in vitro sensitivity of MM cells to bendamustine. These observations represented the rationale for our protocol design namely to evaluate the combination bendamustine (70 mg/m2 days 1, 8), bortezomib (1.3 mg/ m2 days 1, 4, 8, 11) and dexamethasone (20 mg days 1-2, 4-5, 8-9, 11-12) (BVD). Cycles were administered every 4 weeks up to four cycles. Patients achieving a response less than a PR were taken off-study. Patients obtaining at least a PR received two additional treatment cycles followed by a 12-months consolidation phase with cycles repeated every 2 months. Therefore, patients with a PR after the induction phase could receive up to 18 months of treatment and up to 12 cycles of BVD. Patients with relapsed/refractory MM of any age, with adequate cardiac, liver and hematological function, not refractory to bortezomib and treated with no more than four previous lines of therapy were enrolled in this prospective, single-arm, open-label, phase II study conducted in 21 Italian centres. The primary endpoint was achievement of a response at least PR after four cycles of BVD and response was assessed according to to IMWG criteria. From March 2011 to June 2012, 75 patients were included. Median age was 68 years (range 41-85), 26.5% had ISS stage 3, 19% IgA myeloma and 9% renal failure. In total, 8 of 36 evaluable patients (22%) had adverse cytogenetics. All patients had received prior treatment with new drugs, including targeted agents such as thalidomide (57%), lenalidomide (54.5%) or bortezomib (46.5%). Patients had received a median of one prior line of therapy (range 1-4), including alkylators (69%), anthracyclines (29%) and ASCT (44%). Twenty-four patients (32%) were refractory to IMIDs. The response rate ≥ PR after four cycles of BVD was 71.5%, including 11 patients with CR (16%), 13 VGPRs (18.5%) and 26 PRs (37%). Also, 14 patients (20%) had disease stabilization while 6 (8.5%) had progressive disease. Median time to response was 1.2 months (range 0.9-1.4 months). Only prior treatment with bortezomib significantly reduced the response rate ≥ PR (54.5% vs 86.5%; P = 0.003). At a median follow-up of 12 months (range 6-24), 30 patients had progressed and 18 had died. Median TTP and PFS were 16.5 months and 15.5 months, respectively while median OS had not been reached and 78% of patients were alive at 1 year. The Cox regression analysis identified prior therapy with bortezomib plus lenalidomide as the only factor that significantly reduced TTP (9 vs 17 months; HR = 4.5; 95% CI = 1.7-12.3; P = 0.005) Grade 3-4 adverse events occurred in 55% of patients leading to therapy reduction in 20% and to protocol discontinuation in 10.5% of patients. The most frequent severe adverse events were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), peripheral neuropathy (8%), gastrointestinal and cardiovascular events (both 6.5%). Compared with younger, patients aged 〉 70 years had a significantly higher incidence of grade 3-4 thrombocytopenia (22% vs 37%; p=0.042) and severe infections (7 vs 19%; p=0.047) and consequently a higher rate of therapy reduction (9% vs 34.5%; p=0.007) and therapy discontinuation (7% vs 15.5%; p=0.043). Moreover, 4/5 early deaths occurred in patients aged more than 70 years. BVD combination is an effective regimen in relapsed-refractory MM patients since it elicits rapid, high (〉 70%) and good quality of response (more than a third of patients achieved CR + VGPR). Moreover, BVD combination is a feasible and well tolerated regimen provided that adapted therapy and adequate antibiotic prophylaxis are employed in patients older than 70 years. Disclosures: Offidani: Mundipharma: Honoraria, Research Funding. Off Label Use: Bendamustine.

Description: Abstract 1835 Poster Board I-861 Five studies demonstrated the superiority of MPT over MP regimen in elderly patients with MM not eligible for transplantation. In particular, one of these studies, showed this figure in patients aged more than 75 years who represent more than one third of MM patients. Nevertheless, in this latter study 42.5% of patients withdrawn from the MPT protocol because of toxicity. Therefore, there is a wide room of improving these results in this troublesome patient population. Using ThaDD regimen, including liposomal pegylated doxorubicin, we reported low haematological and non-hematological toxicity in elderly and

Description: No standard therapy is still available for older patients with multiple myeloma (MM) despite two third of patients aged over 65 years.The combination melphalan-prednisone yields unsatisfactory results and high-dose therapy can be too toxic or unfeasible.Thalidomide has opened up new horizons also for the treatment of older patients with MM.This multicenter study included patients with de novo symptomatic MM older than 65 years regardless of comorbidities, performance status and renal function. All patients received thalidomide 100 mg continuously, pegylated-liposomal doxorubicin (Caelyx®) 40 mg/m2 on day 1 every 28 days, dexamethasone 40 mg on days 1–4 and 9–12.They also were given warfarin 1.25 mg/day for prophylaxis of thromboembolic disease and ciprofloxacin 250 mg twice daily after a high incidence of infections was recognized. Forty-one patients are valuable for response and toxicity so far.Median age was 72 years (range 64–78) and 63% were older than 70 years. Baseline characteristics are the following: clinical stage III in 30 patients (70%), PS〉2 in 7(18%), ISS≥2 in 73%, creatinine≥2 mg/dl in 15%, unfavourable cytogenetics in 33% of patients with a valuable test. Fifteen patients (37%) achieved CR according to the EBMT criteria, 4 (10%) nCR, 4(10%) VGPR, 15(32%) PR, 4(10%) MR and one patient progressed resulting an ORR of 98%.The majority of the best responses were achieved within the first 3 cycles of therapy. Eight patients underwent autologous stem cell transplantation.Side effects were mild or moderate according to NCI scale.Severe non-hematological toxicity consisted of constipation (7%), fatigue (5%), tremors (2%), mucositis (4%).No patients had peripheral neuropathy or PPE more than grade 2. Grade 3–4 neutropenia was seen in 4(10%) of patients but severe infections occurred in 7(17%) without related deaths. DVT occurred in 5 patients (12%) with one case of pulmonary embolism; all cases resolved with common anticoagulant therapies.No patients discontinued the protocol because of toxicity although two patients refused to continue it after the occurrence of pulmonary embolism and septic shock.With a median follow-up of 15 months, EFS and OS at two years were 65% and 70%, respectively.Our study demonstrated that low-dose thalidomide in combination with pegylated-liposomal doxorubicin and high-dose dexamethasone is very effective inducing an ORR and particularly a CR rate higher than those reported with all other treatments, including high-dose therapy.High quality of response positively impacts on EFS and OS. This combination results well tolerated also by older-frail patients but infections and thromboembolic disease require adequate prophylaxis and therapy. An update of these data will be presented.

Description: Multiple myeloma is a complex hematologic malignancy, and despite a survival improvement related to the growing number of available therapeutic options since 2000s, it remains an incurable disease with most patients experiencing relapse. However, therapeutic options for this disease are constantly evolving and immunotherapy is becoming the mainstay of the therapeutic armamentarium of Multiple Myeloma (MM), starting with monoclonal antibodies (MoAbs) as elotuzumab, daratumumab and isatuximab. Elotuzumab, the first in class targeting SLAMF7, in combination with lenalidomide and dexamethasone and daratumumab, directed against CD38, in combination with Rd and with bortezomib and dexamethasone (Vd), have been approved for the treatment of relapsed/refractory MM (RRMM) after they demonstrated excellent efficacy. More recently, another anti-CD38 MoAb named isatuximab was approved by FDA in combination with pomalidomide-dexamethasone (Pd) in the same setting. Many phase II and III trials with regimens containing these MoAbs are ongoing, and when available, preliminary data are very encouraging. In this review we will describe the results of major clinical studies that have been conducted with elotuzumab, daratumumab and isatuximab in RRMM, focusing on phase III trials. Moreover, we will summarized the emerging MoAbs-based combinations in the RRMM landscape.