Abstract: Continuous therapy (CT) prolongs progression-free survival 1 (PFS1; time from random assignment until the first progression or death), but chemotherapy-resistant relapse may negatively impact overall survival (OS). Progression-free survival 2 (PFS2; time from random assignment until the second progression or death) may represent an additional tool to estimate outcome. This study evaluates the benefit of novel agent–based CT versus fixed duration of therapy (FDT) in patients with newly diagnosed myeloma. Methods We included patients enrolled onto three phase III trials that randomly assigned patients to novel agent–based CT versus FDT. Primary analyses were restricted to the intent-to-treat population eligible for CT (patients progression free and alive at 1 year after random assignment). Primary end points were PFS1, PFS2, and OS. All hazard ratios (HRs) and 95% CIs were adjusted for several potential confounders using Cox models. Results In the pooled analysis of the three trials, 604 patients were randomly assigned to CT and 614 were assigned to FDT. Median follow-up was 52 months. In the intent-to-treat CT population, CT (n = 417), compared with FDT (n = 410), significantly improved PFS1 (median, 32 v 16 months, respectively; HR, 0.47; 95% CI, 0.40 to 0.56; P 〈 .001), PFS2 (median, 55 v 40 months, respectively; HR, 0.61; 95% CI, 0.50 to 0.75; P 〈 .001), and OS (4-year OS, 69% v 60%, respectively; HR, 0.69; 95% CI, 0.54 to 0.88; P = .003). Conclusion In this pooled analysis, CT significantly improved PFS1, PFS2, and OS. The improvement in PFS2 suggests that the benefit reported during first remission is not cancelled by a shorter second remission. PFS2 is a valuable end point to estimate long-term clinical benefit and should be included in future trials.

Abstract: 8002 Background: High and comparable rates of MRD negativity were seen in NDMM pts after 4 28-day induction cycles with KRd followed by ASCT and 4 KRd consolidation (KRd_ASCT_KRd) and after 12 KRd cycles (KRd12), showing the superiority of both regimens over KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd) (Gay F ASH 2018). Here we evaluated the benefit of KRd_ASCT_KRd vs KRd12 in specific subgroups of pts. Methods: 474 NDMM pts ≤65 years were randomized to KRd_ASCT_KRd or KRd12 or KCd_ASCT_KCd. We compared rate of ≥VGPR, ≥CR, sCR, MRD negativity (centralized, second generation flow cytometry, sensitivity 10 -5 ) after consolidation with KRd_ASCT_KRd vs KRd12 in patients with R-ISS 1 and R-ISS 2/3. Since high-risk pts may sometimes respond rapidly, but then relapse early, we also analyzed the rate of early relapse ( 〈 18 months from randomization). We performed a multivariate logistic regression analysis to evaluate factors predictive of early relapse. Results: Median follow-up was 25 months. Rates of ≥VGPR, ≥CR, sCR, MRD negativity were comparable between KRd_ASCT_KRd and KRd12 overall, in pts with R-ISS Stage 1 and with R-ISS Stage 2/3 (Table). A significantly lower number of pts experienced early relapse with KRd_ASCT_KRd vs KRd12 (12 pts [8%] vs 26 pts [17%] ; P=0.015). This difference was mainly related to a significantly lower rate of early relapse in R-ISS Stage 2/3 pts receiving KRd_ASCT_KRd vs KRd12 (11 pts [12%] vs 22 pts [23%] ; P=0.05); no difference was seen in R-ISS 1 (0 vs 2 pts). In multivariate regression analysis, KRd_ASCT_KRd vs KRd12 reduced the risk of early progression (OR 0.42; P=0.021); R-ISS Stage 2 (OR 3.6; P=0.001) and R-ISS Stage 3 (OR 4.85; P=0.003) increased the risk compared with R-ISS 1. Conclusions: KRd-ASCT-KRd and KRd12 were equally effective in inducing high-quality responses, with about 50% of high-risk pts achieving MRD negativity. In high-risk pts ASCT reduced the risk of early relapse. Clinical trial information: NCT02203643. [Table: see text]

Abstract: The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). Patients and Methods Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. Results ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum β 2 -microglobulin level 〈 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III (n = 295), including ISS stage III (serum β 2 -microglobulin level 〉 5.5 mg/L) and high-risk CA or high LDH level; and R-ISS II (n = 1,894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively. Conclusion The R-ISS is a simple and powerful prognostic staging system, and we recommend its use in future clinical studies to stratify patients with NDMM effectively with respect to the relative risk to their survival.

Abstract: Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those & gt;75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in & gt;75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in & gt;75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p & lt;0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: 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. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Abstract: In newly diagnosed multiple myeloma (MM) patients, the combination melphalan, prednisone and thalidomide (MPT) induces a fast tumor response with a high response rate, but evidence that this translate into improved outcome is limited. This multicenter trial compared the efficacy and the toxicity of oral MPT with oral melphalan and prednisone (MP) in previously untreated patients. From January 2002 to December 2004, we randomised 255 patients, who were older than 65 years of age (median age 72). Data analysis was performed on July 2005. The MPT regimen included oral melphalan (4 mg/m2 for 7 days) and prednisone (40 mg/m2 7 days) for six four week cycles plus thalidomide (100 mg per day continuously until any sign of relapse or progressive disease) The MP regimen was as MPT without thalidomide. Patients who were not assigned to receive thalidomide were permitted to cross over to receive thalidomide after relapse or disease progression. Patients treated with MPT experienced higher response rates and a longer time to progression (primary end points) than patients who did not receive thalidomide. The overall response rate was 76% for MPT and 48% for MP alone (P & lt;0.0001), and the near complete response rates were 28% and 7%, respectively (P & lt;0.0001). Median progression free survival in the MPT and in the MP groups was 33 months and 14 months, respectively (hazard ratio, 0.47; P & lt;0.001). MPT increase median progression free survival by almost 19 months. The 2-yr survival rate was 82% in MPT patients and 65% in MP patients (hazard ratio, 0.68; P=0.2). In MPT group, 33 patients did not complete the 6 courses because of progression disease (9), toxicity (16), death (2), and withdrawal of consent or lost to follow-up (6). In MP group, 32 patients did not complete the 6 courses because of progression disease (19), toxicity (3), death (3), and withdrawal of consent or lost to follow-up (7). By looking at those patients who completed the assigned 6 cycles in both arms, the 2-yr survival rate was 90% in MPT patients and 71% in MP patients, the difference was statistically significant (hazard ratio, 0.39; P & lt;0.01). Grade 3 or 4 adverse events were reported in 49% of patients treated with MPT and in 25% of those treated with MP: they included thromboembolism (12% versus 2% of patients), infections (10% versus 1%), peripheral neuropathy (10% versus 1%), and hematologic toxicity (22% versus 25%) respectively. In the first 64 patients who received MPT, grade 3–4 adverse events were reported in 58% of patients. In the last 65 MPT patients, the incidence of grade 3–4 adverse events was 40%. By comparing the first cohort with the second one, thromboembolism dropped from 22% to 3% (P & lt;0.01) and neurotoxicity from 13% to 8% (P=NS), respectively. The oral MPT was superior to the standard MP in patients with newly diagnosed myeloma. The adequate mangement of side effects reduced toxicity.

Abstract: Introduction. Lenalidomide (RevlimidR) is a novel, orally active immunomodulatory drug effective for the treatment of refractory myeloma. In this multicenter trial, we evaluate the potential additive and synergistic effect of the combination RevlimidR, melphalan and prednisone (R-MP). Materials and Methods. Patients (pts) with newly diagnosed symptomatic multiple myeloma older than 65 years were treated with 9 courses of RevlimidR (5–10 mg/day for 21days every 4–6 weeks) plus MP (melphalan 0.18–0.25 mg/kg and prednisone 2 mg/kg for 4 days every 4–6 weeks). The trial was designed to define the toxicity profile of R-MP and to analyze the efficacy of this combination. Four different dose levels were tested: 1. melphalan 0.18 mg/kg + RevlimidR 5 mg/day; 2. melphalan 0.25 mg/kg + RevlimidR 5 mg/day; 3. melphalan 0.18 mg/kg + RevlimidR 10 mg/day; 4. melphalan 0.25 mg/kg + RevlimidR 10 mg/day. Each cohort included 6 pts. Dose limiting toxicity (DLT) was defined as: any grade ≥ 3 non-hematologic toxicity; grade 4 neutropenia lasting & gt;7 days; any other grade 4 hematologic toxicity and any treatment delay due to toxicity that occurred during the first cycle. All pts received ciprofloxacin and aspirin as prophylaxis. Results. At present, 24 pts (median age 72, range 61–77) received at least one R-MP course and were evaluated. No DLTs were observed in the first 2 dose levels; 1 DLT was observed with melphalan 0.18 mg/Kg and RevlimidR mg/kg (grade 4 neutropenia lasting & gt; 7 days); 2 DLTs were reached with melphalan 0.25 and RevlimidR 10 mg (1 neutropenic fever, 1 grade 3 cutaneous toxicity). After 1 cycle of R-MP, no one was in complete remission (according to the EBMT/IBMTR criteria), 2 pts (9.5%) showed a myeloma protein reduction of 75–99%, 7 pts (28.6%) a response of 50–74%, and 15 (61.9%) a response of & lt;50% (1 of these pts showed a 30% reduction in the size of soft tissue plasmacytomas), no disease progressions were observed. After 3 cycles of R-MP, myeloma protein reduction of 75–99% was detected in 1 patients (11,1%), response of 50–74% in 8 patients (55.6%) and response & lt;50% in 5 patients (33.3%), no disease progressions were observed. Grade 3 or 4 adverse events were reported in 9 patients (35%). They included: 1 thrombo-embolism (4.2%); 5 grade 4 neutropenias (20.9%) ;4 grade 3 neutropenias (16.7%); 4 grade 3 thrombocytopenias (16.7%); 1 febrile neutropenia (4.2%); 2 grade 3 dermatological toxicities (8.3%); 1 grade 3 metabolic toxicity (4.2%) and 1grade 4 metabolic toxicity (4.2%). One pt discontinued RevlimidR because of grade 3 dermatological toxicity. Dose- reduction was required in 4 pts (1 grade 4 neutropenia & gt;7 days, 1 treatment delay due to toxicity, 2 grade 3 dermatological toxicities). Conclusions. R-MP was well tolerated with a manageable toxicity. Significant response rate was observed. It represents a feasible and promising approach for newly diagnosed pts who are not candidates for transplant. Fifteen additional pts were treated with the fix dose of melphalan 0.18 mg/kg + RevlimidR 10 mg/day, results are too premature to assess efficacy. An update of these data will be presented.

Abstract: Abstract 620 Background. The combination of bortezomib-melphalan-prednisone (VMP) is a new standard of care for elderly newly diagnosed multiple myeloma. This phase 3 study compared the 4 drug combination bortezomib-melphalan-prednisone-thalidomide followed by maintenance bortezomib-thalidomide (VMPT-VT) with VMP alone. Methods. Patients (N=511) older than 65 years were randomized to receive nine 6-week cycles of VMPT-VT (N=254; induction: bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, thalidomide 50 mg d 1–42; maintenance: bortezomib 1.3 mg/m2 every 14 days and thalidomide 50 mg/day) or VMP (N=257) alone. In March 2007, the protocol was amended: both VMPT-VT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 d 1,8,15,22, all cycles). The primary end point was progression-free survival (PFS). Results. All patients have been evaluated in intention-to-treat. Patient characteristics were similar in both groups, median age was 71 years. The response rates were superior in the VMPT-VT group with a complete remission (CR) rate of 38% vs 24% (p=0.0008). After a median follow-up of 26.1 months, the 3-year PFS were 55% in patients receiving VMPT-VT and 38% in those receiving VMP (HR 0.65, 95% CI 0.49–0.85, P=0.002, Table). The 3-year time-to-next-therapy were 69% with VMPT-VT and 55% with VMP (HR 0.60, 95% CI 0.42–0.85, P=0.004). The 3-year overall survival was 86% with VMPT-VT and 84% with VMP (HR 0.88, 95% CI 0.53–1.45, P=0.62). The achievement of CR was a strong predictive factor of longer PFS in both groups (P=0.0001): in VMPT-VT arm, 3-year PFS was 66% in patients who obtained CR and 47% in those achieving PR; in VMP arm, it was 70% and 30%, respectively. The PFS benefit of VMPT-VT was seen consistently across different subgroups defined by creatinine clearance, LDH and bortezomib schedule; by contrast, in patients older than 75 years (HR 0.87; 95% CI 0.54–1.43, P=0.59) and in those at increased risk of disease progression, defined as presence of cytogenetic abnormalities [t(4;14) or t(14;16) or del17p] and ISS 3 (HR 1.35; 95% CI 0.45–4.06, P=0.60), VMPT-VT seemed not to add any significant PFS advantage to VMP. Grade 3–4 neutropenia (38% vs. 28%, p=0.02), cardiological events (10% vs. 5%, p=0.04) and thromboembolic events (5% vs. 2%, p=0.08) were more frequent among patients assigned to the VMPT-VT group; treatment-related deaths were 4% with VMPT-VT and 3% with VMP. In both groups, the once-weekly infusion of bortezomib significantly reduced the incidence of severe sensory peripheral neuropathy from 16% to 3% (p 〈 0.0001). One hundred and forty-nine VMPT-VT patients were assessable for maintenance treatment. After a median duration of maintenance of 14.4 months, the PR rate was 90%, including 45% CR. The 1-year landmark analysis of PFS in patients completing the 9 induction cycles, showed a 2-year PFS of 63% in the VMPT-VT group and 40% in the VMP group, demonstrating that maintenance with VT reduced the risk of disease progression of 51% (HR 0.49, 95% CI 0.33–0.72, p=0.0003, Figure). This advantage was less evident in patients older than 75 years (HR 0.97, 95% CI 0.52–1.78, P=0.91) and in those with high-risk of disease progression, defined as presence of cytogenetic abnormalities and ISS 3 (HR 1.31, 95% CI 0.22–7.85, p=0.77). Continuous therapy with VT had favourable safety profile: 3% of patients experienced grade 3–4 hematological toxicity, 5% grade 3–4 peripheral neuropathy and 7% discontinued due to adverse events. Conclusion. In summary the current results indicate that: 1. VMPT-VT prolonged PFS with an unprecedented 3-year PFS of 55% in elderly patients; 2. once-weekly infusion of bortezomib improved safety without affecting outcome; 3. higher dose-intensity regimens seemed to be less effective in frail patients (≥ 75 years) and 4. maintenance therapy with VT further improved PFS with a good safety profile. Disclosures: 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. Bringhen:Celgene: Honoraria; Janssen-Cilag: Honoraria. Patriarca:Celgene: Honoraria; Janssen Cilag: Honoraria; Roche: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Petrucci:Celgene: Honoraria; Janssen Cilag: Honoraria. Musto: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.

Abstract: Cardio-vascular (CV) events are common in patients (pts) with myeloma (MM) and may occur as a result of age-related comorbidities, the disease itself or as a complication of anti-MM treatment, including proteasome inhibitors.Carfilzomib is a novel second generation proteasome inhibitorapproved as a single agent and in combination with lenalidomide and dexamethasone for the treatment of relapsed MM. Here, we present the results of an integrated CV safety analysis of 148 newly diagnosed, elderly or transplant-ineligible pts enrolled in 3 phase I/II studies with the combination of Carfilzomib, cyclophosphamide and dexamethasone(IST-CAR-506, IST-CAR-561, IST-CAR-601).In all trials cyclophosphamide 300 mg/m2 was administered orally on days 1, 8, 15 and dexamethasone 40 mg was administered orally once weekly. Carfilzomib was administered intravenously at the dose of 36 mg/m2 on days 1, 2, 8, 9, 15, 16 in the IST-CAR-506 trial; at 3 dose levels escalated from 45 to 70 mg/m2 on days 1, 8, 15 in the IST-CAR-561 trial and on days 1, 2, 8, 9, 15, 16 in the IST-CAR-601 trial. In all studies, after completing 9 28-day cycles, pts received 28-day maintenance cycles with Carfilzomib until disease progression or intolerance. Adverse events (AEs) were graded based on NCI-CTCAE v4. Median age was 72 years (range 55-85), 38 pts (26%) were older than 75 years. The median follow-up was 21 months. Overall, any grade CV AEs were reported in 62 pts (42%): 40/110 pts (36%) younger than 75 years and 22/38 (58%) older than 75 years (p=0.02). The more frequent events were hypertension, aggregated cardiac failure events, thromboembolic events and arrhythmia (Table 1). Grade ≥ 3 events occurred in 29 pts (30%): 17/110 pts (15%) younger than 75 years and 13/38 (34%) older than that (p=0.01). Aggregated cardiac failure events of any grade were reported in 10 pts (7%), thromboembolic events in 5 pts (3%), hypertension in 4 pts (3%) and arrhythmia 2 pts (1%). In pts younger than 75 years, the most frequent grade ≥ 3 AEs were hypertension (10 patients, 9%) and dyspnea (11 patients, 10%). In pts older than 75 years, the most frequent grade ≥ 3 AEs were hypertension and pulmonary edema (5 pts each, 13%). Importantly, 34% of pts who experienced CV AEs had hypertension at baseline or developed it during treatment compared to 14% of pts who did not experience CV AEs. Diabetes was more frequent (33%) in pts older than 75 years who developed CV AEs compared to 10% of pts older than 75 years who did not report any CV AEs or those younger than 75 years. No difference was observed among different doses or different schedules of Carfilzomib. Among pts who developed a CV AE, one third had a Carfilzomib dose reduction or discontinuation (Table 1) compared to 12-18% of pts who did not experience CV toxicity (p 〈 0.0001). Overall, the risk of CV toxicity was lower during maintenance: 21 pts of 97 who started maintenance (22%) developed any grade CV events. This improvement was evident only in pts younger than 75 years: 11/75 patients younger than 75 years (15%) had CV events compared to 10/22 (45%) older than 75 years (Figure 1). The most frequent CV AE during maintenance was hypertension (12%), regardless of age. Only 5 pts (5%) reduced Carfilzomib dose during maintenance. Five (3%) CV-related deaths were documented: 4 during induction and 1 during maintenance. All of them were possibly related to Carfilzomib (atrial fibrillation, heart failure, cardiac arrest, sudden death, pulmonary embolism). The occurrence of any CV AE during induction increased the mortality for any cause by twofold, regardless of age: the 2-year overall survival was 70% in patients who experienced CV AE and 82% in those who did not (HR 2.01, 95% CI 0.99-4.07, p=0.04). The risk of CV AEs during treatment with Carfilzomib is significantly higher in pts older than 75 years and the most important risk factor, regardless of age, is hypertension. Developing CV toxicity increases the need for dose reduction or drug discontinuation with a negative impact on overall survival. Elderly pts should be carefully assessed before starting treatment with 24 hour blood pressure monitoring. During treatment, baseline vital signs should be recorded and medications of blood pressure should be targeted promptly to keep blood pressure below 140/80 mmHg. With these simple actions, these AEs may be prevented or managed proactively and pts can derive maximum benefit from their treatment with Carfilzomib. Disclosures Bringhen: Mundipharma: Other: ADVISORY BOARD; Amgen: Other: ADVISORY BOARD; Janssen-Cilag: Honoraria; Celgene: Honoraria; BMS: Honoraria; Karyopharm: Other: ADVISORY BOARD. Petrucci:Janssen-Cilag: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Caravita di Toritto:Janssen-Cilag: Honoraria. Ria:BMS: Speakers Bureau; BMS: Speakers Bureau; Italfarmaco: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Janssen-Cilag: Other: Advisory Board, Speakers Bureau; Binding Site: Speakers Bureau. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Foà:Janssen-Cilag: Consultancy, Speakers Bureau; Genetech: Consultancy; Roche: Consultancy, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Corradini:Celgene: Honoraria, Speakers Bureau; Janssen-Cilag: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Sanofi Aventis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Gentium: Honoraria, Speakers Bureau. Gaidano:Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Sonneveld:Celgene: Other: Advisory board, Research Funding; Millennium: Other: Advisory board, Research Funding; Onyx: Other: Advisory board, Research Funding; Janssen-Cilag: Other: Advisory board, Research Funding. Boccadoro:Novartis: Honoraria, Research Funding; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbivie: Honoraria; Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; CELGENE: Honoraria, Research Funding.

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