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: Introduction : a formal comparison between Lenalidomide-Dexamethasone (Rd) and Lenalidomide-Prednisone plus Melphalan (MPR) or Cyclophosphamide (CPR) has not been performed yet. We compared Rd vs. MPR vs. CPR in newly diagnosed multiple myeloma (NDMM) patients ≥65 years old in a multicenter phase III trial. Per protocol, upfront dose reductions of Dexamethasone, Melphalan and Cyclophosphamide were performed, according to patients age ( ≤75 years vs. 〉 75 years). The primary endpoint was progression-free survival (PFS). Methods : 662 patients with NDMM were randomized to receive nine 28-day cycles of Rd (n=222), MPR (n=218) or CPR (n=222). Rd: lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15,22 in patients 65-75 years old and 20 mg in those 〉 75 years; MPR: lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in patients 65-75 years old and 0.13 mg/Kg in patients 〉 75 years; prednisone 1.5 mg/Kg for 4 days; CPR: lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in patients 65-75 years old and 50 mg every other day in patients 〉 75 years; prednisone 25 mg every other day. After induction, patients were randomized to receive maintenance with lenalidomide alone (R) or with prednisone (RP). Results : Patients characteristics were well balanced. Eighty-three (37%) patients in the Rd, 86 (39%) in the MPR and 80 (36%) in the CPR groups were older than 75 years. In intention to treat analysis, after a median follow-up of 31 months, no difference in PFS and overall survival (OS) was observed. Median PFS was 23 months in Rd, 27 months in MPR and 23 months in CPR (Rd vs MPR p=0.216; Rd vs CPR p=0.872; MPR vs CPR p=0.148). Median OS was not reached and was 73% in Rd, 67% in MPR and 72% in CPR at 3 years (Rd vs MPR p=0.663; Rd vs CPR p=0.754; MPR vs CPR p=0.448). A subgroup analysis, according to age was performed. No difference in response rate was observed. In patients ≤75 years, median PFS was 23 in Rd, 30 in MPR and 23 months in CPR (Rd vs MPR, p 〈 0.04; Rd vs CPR p=0.897; MPR vs CPR, p 〈 0.05). Median OS was not reached and was 75% in Rd, 76% in MPR, 77% in CPR at 3 years (Rd vs MPR p=0.251; Rd vs CPR p=0.280; MPR vs CPR p=0.975). In patients 〉 75 years, no PFS difference was noticed: median PFS was 22 in Rd, 18 in MPR, 21 months in CPR (Rd vs MPR p=0.572; Rd vs CPR p=0.699; MPR vs CPR p=0.914). An OS advantage was reported with Rd: median OS was not reached in Rd patients, and was 37 and 43 months in the MPR and CPR groups, respectively (Rd vs MPR p=0.04; Rd vs CPR p=0.430; MPR vs CPR p=0.323). The rate of at least one hematologic grade 3-4 adverse event was 29% in Rd, 66% in MPR, 33% in CPR patients ≤ 75 years and 29% in Rd, 70% in MPR, 33% in CPR patients 〉 75 years (MPR vs Rd/CPR p 〈 0.0001). No difference was observed in extra-hematologic adverse events: 25% in Rd, 24% in MPR and 25% in CPR patients ≤75 years; 29% in Rd, 35% in MPR, 34% in CPR patients 〉 75 years. Conclusion : this trial compared for the first time Rd, MPR and CPR in elderly NDMM. In all patients, the addition of alkylating agent to Lenalidomide-steroid combination did not show any advantage on PFS and OS. In a subgroup analysis, safety and efficacy data suggest that triplet regimens may be indicated in patients ≤75 years, while a doublet regimens for those 〉 75 years. The MPR combination showed a PFS advantage in patients ≤75 years, with a higher incidence of hematologic toxicity and SPM. In patients 〉 75 years an OS advantage was reported with Rd, mainly due to a higher efficacy of salvage treatments. Updated results will be presented at the meeting. Disclosures Off Label Use: Use of Lenalidomide as off label. Bringhen:Onyx: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Offidani:Mundipharma: Honoraria; Sanofi: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Patriarca:Merck Sharp & Dohme: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Boccadoro:Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen and Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo:Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Honoraria; Amgen: Consultancy, Honoraria; Array BioPharma: Honoraria.

Abstract: 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

Abstract: Several trials have shown the superior impact of high-dose melphalan (usually 200 mg/m2, MEL200) versus standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m2, MEL100) was also superior to the standard dose, but MEL100 has not been clinically compared with MEL200 in a randomized study. In this prospective, randomized, phase III trial, we compared the efficacy and toxicity of MEL200 and MEL100. The primary end points were complete remission (CR) rate, event-free survival (EFS) and incidence of gastrointestinal toxicity, infections and treatment-related mortality (TRM). Inclusion criteria were previously untreated myeloma, aged ≤ 65 and Durie and Salmon stage II or III. Exclusion criteria were abnormal pulmonar, cardiac, liver and renal function, HBV, HCV, or HIV positivity, concomitant cancer or psychiatric disease. The institutional review board approved the protocol and written informed consent was obtained from all patients. All patients received 2 cycles of 28-day-dexamethasone-doxorubicin-vincristine (doxorubicin 50 mg/m2 day 1, vincristine 1 mg day 1, dexamethasone 40 mg days 1–4) and 2 cycles of cyclophosphamide (4 g/m2, day 1) followed by stem cell harvest. MEL200 patients was conditioned with 2 cycles of melphalan 200 mg/m2 and MEL100 patients with 2 courses of melphalan 100 mg/m2, both followed by stem cell reinfusion. Two-hundred and ninety-eight patients (median age 57) were randomized, 149 to MEL200 and 149 to MEL100. All patients were evaluated for response, EFS and OS. Patient characteristics were similar in both groups. Chromosomal 13 was deleted in 69% of MEL200 and 45% of MEL100 patients (p=0.015). Ninety-six patients completed tandem MEL200; 103 tandem MEL100. In intention-to-treat analysis, the very good partial response rate was higher in MEL200 group (37% versus 21%, p=0.003), but CR was 15% in the MEL200 group and 8% in the MEL100 group (p=0.07). After a median follow-up of 30.5 months, the 3-years EFS was 46% in the MEL200 and 26% in the MEL100 group (HR=0.7, 95% CI 0.51–0.97, p=0.03). The 3-years overall survival (OS) was 81% in the MEL200 and 73% in the MEL100 group (HR=0.69, 95% CI 0.42–1.13, p=0.14). Duration of grade 4 neutropenia and thrombocytopenia was comparable, but a higher proportion of MEL200 patients required platelet transfusions (p=0.002). Grade 3–4 non-hematologic adverse events were more frequent in the MEL200 patients (38% versus 19%, p 〈 0.0001). The incidence of grade 3–4 mucositis was 16% after MEL200 and 3% after MEL100 (p 〈 0.0001). The incidence of severe gastrointestinal toxicity was 19% after MEL200 and 2% after MEL100 (p 〈 0.0001). The incidence of grade 3–4 infections and of TRM was similar in both groups. In conclusion, MEL200 resulted in a significantly higher very good partial response rate. This translated in a superior EFS, but not OS.