ALBERT

Description: Background Carfilzomib is a novel second generation proteasome-inhibitor with significant anti-MM activity and favorable toxicity profile. In a recent phase 1/2 study in relapsed/refractory patients (pts) a weekly schedule of carfilzomib in combination with dexamethasone showed to be effective (overall response rate of 77%) and safe (ASCO 2015). The ongoing phase 3 ARROW study is comparing once- with twice-weekly carfilzomib. In the newly diagnosed setting, no data are available on weekly carfilzomib. We designed a phase 1/2 study of weekly carfilzomib in combination with cyclophosphamide and dexamethasone (wCCyd) for newly diagnosed MM pts. Results of the dose-escalation phase 1 portion of study were previously reported (Palumbo A et al, Blood 2014), the maximum tolerated dose of weekly carfilzomib was established as 70 mg/m2. Here we report efficacy and safety results of the phase 2 portion of the study. Methods Newly diagnosed pts ineligible for autologous stem-cell transplantation due to age or co-morbidities were enrolled in the phase 2 portion of the study. Pts received IV carfilzomib at the maximum tolerated dose 70 mg/m2 on days 1, 8, 15 combined with oral cyclophosphamide at 300 mg/m2 on days 1, 8, 15 and oral dexamethasone at 40 mg on days 1, 8, 15, 22, in 28-daycycles. After the completionof 9 cycles, pts received 28-day maintenance cycles with carfilzomib at 70 mg/m2 on days 1, 8, 15 until disease progression or intolerance. The primary objectives were to determine the efficacy and safety of wCCyd. The secondary objectives included the evaluation of time to progression, progression-free survival, time to next therapy and overall survival. Response was assessed according to the modified International Uniform Response Criteria. Adverse events (AEs) were graded following NCI-CTCAE v4. Results As of July 15, 2015, 47 newly diagnosed MM pts were enrolled in the phase 2 portion of the study. Median age was 72 years, 23% of pts were older than 75 years, 30% had ISS stage III, 34% had unfavorable FISH profile [t(4;14) or t (14;16) or del17p or amp1]. Toxicityand response data were available in 40 pts, who completed atleast the first cycle; 7 pts were still receiving their first cycle of treatment. Pts received a median of 6 cycles (range 1-9). Overall, 80% of pts achieved at least a partial response, 60% at least a very good partial response, and 28% a near complete response. Responses improved over time (Table 1). During the study, 9 pts progressed or died, the progression-free survival at 1 year was 75%. Grade (G) 3-4 drug-related adverse events included neutropenia (22%, 9 pts), thrombocytopenia (7%, 3 pts), infection (10%, 4 pts), acute pulmonary edema (5%, 2 pts), creatinine increase (5%, 2 pts), fever (2.5%, 1 pt), fatigue (2.5%, 1 pt) and headache (2.5%, 1 pt). G1-2 hypertension was reported in 6 pts (15%). No peripheral neuropathy was reported. Overall, the wCCyd regimen was well tolerated, 4 pts (10%) required carfilzomib dose-reduction (G3 hematologic toxicities [2 pts], G3 headache [1 pt] and G2 fatigue [1 pt]) and 9 pts (22%) required treatment discontinuation due to adverse events (2 infections, 1 acute pulmonary edema, 1 creatinine increase, 1 fever, 1 pt condition, 1 second tumor, 1 pericardial effusion, 1 sudden death). Conclusions This is the first prospective study evaluating once-weekly carfilzomib in treatment-naïve MM. wCCyd therapy appears safe and effective in newly diagnosed MM pts. Responses became deeper with subsequent cycles and toxicities were manageable. The response rate observed with weekly carfilzomib compares favorably with similar studies with standard twice-weekly carfilzomib infusion. Updated results will be presented at the meeting. Table 1. 2nd cycle 6th cycle 9th cycle Complete Response 17% 26% 33% At least near Complete Response 29% 39% 40% At least Very Good Partial Response 66% 82% 87% At least Partial Response 86% 87% 87% Disclosures Bringhen: Janssen-Cilag, Celgene, Novartis: Honoraria; Onyx: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use off-label of drugs for the dose and/or schedule and/or association. Larocca:Janssen-Cilag, Celgene: Honoraria. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Gaidano:Celgene, Onyx: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: 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; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria.

Description: Abstract 3029 Background. In a recent phase 3 trial, bortezomib–melphalan – prednisone–thalidomide followed by maintenance treatment with bortezomib–thalidomide (VMPT-VT) demonstrated superior efficacy compared with VMP. Peripheral neuropathy (PN) was the most important dose limiting toxicity. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions. This post-hoc analysis assessed the impact of bortezomib dose-modification schedule on clinical outcomes and safety. Methods. Patients (N=511) older than 65 years were randomized to receive nine 6-week cycles of VMPT-VT (N=254; induction:V 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; M 9 mg/m2 d 1–4, P 60 mg/m2, d 1–4, T 50 mg d 1–42; maintenance: V 1.3 mg/m2 every 14 days and T 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). Patients receiving VMPT-VT and VMP were pooled together and stratified according to the once-weekly or twice-weekly infusion modality; analyses were also conducted for patients receiving VMP only, to eliminate the influence of thalidomide and of maintenance on efficacy and safety. Results. Patients were evaluated in intention-to-treat: 372 patients received once-weekly and 139 twice-weekly bortezomib infusion. Patient characteristics were similar in the two groups, median age was 71 years. The efficacy data did not appear to be affected by the bortezomib schedule. Overall response rates were 85% with once weekly and 86% with twice- weekly schedule (P = .78), including CR rates of 30% and 35% (P = .27).Three-year PFS was 50% in the once-weekly and 47% in the twice-weekly group (P = 1.00), and 3-year OS was 88% and 89%, respectively (P = .54). Similar outcome was seen in the analyses restricted to VMP patients: CR rates were 23% with once-weekly and 27% with twice-weekly schedule (P = .54), 3-years PFS was 46% in once-weekly and 39% (P = .86) in twice-weekly group and 3-years OS was 87% and 89% (P = .47), respectively. The incidence of grade 3/4 hematologic toxicity was similar in the two groups (44% vs 45%, P = .83), but severe thrombocytopenia was slightly less common in the once-weekly patients (19% vs 26%, P = .08).The incidence of non-hematologic grade 3/4 adverse events was significantly reduced in the once-weekly: 35% vs 51% (P = .003). Grade 3/4 gastrointestinal events (6% vs 11%, P = .08), severe systemic events (4% vs 7%, P = .09) and grade 3/4 dermatologic events (2% vs 7%, P = .006) were less frequent in patients receiving once-weekly bortezomib. There was a significantly reduced overall incidence of grade 3/4 PN (8% vs 28%, P 〈 .001) in the once-weekly group. The median time to onset of grade 3/4 sensory PN was 4.3 months in the once-weekly group and 3.2 months in the twice-weekly group (P = .10). The cumulative incidence of sensory PN appeared to plateau after 12 months of therapy in both groups. Rates of discontinuations (5% versus 15%) and dose reductions (15% versus 41%) due to PN were also significantly lower in the once-weekly group (P 〈 .001). These results were reflected in analysis restricted to VMP patients, in which the incidence of grade 3/4 PN (7% vs 29%, P 〈 .001), the discontinuation rate (4% vs 16%, P = 0.002), and the dose reductions rate (15% vs 41% P 〈 0.001) were significantly lower in once-weekly group. Despite the cumulative planned dose being lower in the once-weekly group (46.8 vs 67.6 mg/m2), the delivered cumulative dose of bortezomib was similar in the two groups (39.4 mg/m2 vs 40.1 mg/m2). No association of PN with age or other baseline characteristics was outlined. The only significant factor influencing the incidence of PN was the reduction of bortezomib infusion from twice- to once-weekly (p

Description: Background The introduction of new agents has substantially changed the management of patients with multiple myeloma (MM). PATIENTS AND METHODS: We evaluated retrospectively 69 symptomatic newly diagnosed transplant-ineligible MM patients treated at our Institute, between 2004 and 2012, with Melphalan and Prednisone (MP) plus Thalidomide (MPT; 23 patients) or plus Bortezomib (MPV; 30 patients) or plus Lenalidomide (MPR; 16 patients). There were 37 men and 32 woman, median age was 73 years (range 65-84) with 20 patients 〉75 years, 19 (27.5%) were in stage III according to ISS, 12 (17%) had renal failure (creatinine 〉1.5 mg/dl at baseline), 7 (10%) an underlying diabetes mellitus and 36 (52%) a cardiovascular disease. Melphalan was given at 9 mg/m2 and Prednisone at 60 mg/m2 orally on days 1-4; Bortezomib at 1.3 mg/m2 intravenously on days 1, 4, 8, 11, 22, 25, 29, 32 for the first 4 cycles and thereafter on days 1, 8, 15, 22; Lenalidomide at 10 mg on days 1-21 and Thalidomide 100 mg/daily were administered orally. All patients received antibacterial prophylaxis; thromboprophylaxis and antiviral prophylaxis were administered to patients treated with IMIDs and Bortezomib, respectively. Aims To evaluate the safety and efficacy within the MPT-, MPV- and MPR-treated groups. Results The overall response rates ( ≥ partial response), according to the IMWG criteria, were 20/23 (87%) in the MPT group, 26/30 (87%) in the MPV group, 11/16 (68%) in the MPR group (including 3, 9, 2 very good partial response and 2, 3, 2 complete response/near complete response, respectively). The median PFS was 29 months (95% CI: 18-NA months) for patients who received MPT, 24 months (95% CI: 20-32 months) with MPV and 21.5 months (95% CI: 17-NA months) with MPR, with no significant differences between the three regimens. Among the 69 patients, the overall grade 3-4 hematologic and non-hematologic toxicities were 36% and 43%, respectively. The most common non-hematologic toxicities included all grades of peripheral neuropathy (14% with MPV, 7.2% with MPT and none with MPR), grade 3-4 infections (7.2% with MPV, 4.3% with MPT and 2.9 with MPR) and grade 3-4 cardiovascular disease (4.3% with MPT, 1.4% with MPV and none with MPR). With the use of thromboprophylaxis in all IMID-treated patients, we observed only one deep vein thrombosis in one patient treated with MPT. Conclusions MPT, MPV and MPR are highly active and well tolerated regimens for previously untreated MM patients. The rates of treatment-associated thrombocytopenia and neutropenia were similar between the 3 different regimens and proved transient, predictable and manageable; few patients required supportive care. The results obtained using MP plus one of the recently developed drugs confirm that MPT, MPV and MPR should be considered the standard of care in the frontline treatment of newly diagnosed transplant-ineligible MM patients. Disclosures: Petrucci: Janssen and Celgene: Honoraria; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees.

Description: Background Carfilzomib is a novel second generation proteasome-inhibitor with significant anti MM activity and favorable toxicity profile, including very limited neurotoxicity and neutropenia. This Phase I/II study was designed to determine the maximum tolerated dose (MTD) of once weekly carfilzomib combined with cyclophosphamide-dexamethasone (wCCd) and to assess safety and efficacy of this combination in elderly patients with newly diagnosed MM. Here we report the first findings from the Phase I dose-escalation and expansion portions. Enrolment in the phase II portion is ongoing. Methods In the Phase I, the standard 3+3 dose-escalation scheme was adopted, with Carfilzomib as the only escalating agent starting at 45 mg/m2 (level 0), maximal planned dose 70 mg/m2 (level 2), and 36 mg/m2, if needed (level -1), given IV on days 1, 8, 15 in 28-day cycles. Oral cyclophosphamide was administered at 300 mg/m2 on days 1, 8, 15 and oral dexamethasone at 40 mg on days 1, 8, 15, 22 for all dose levels. Dose escalation of Carfilzomib was based on dose-limiting toxicities (DLTs) occurring in cycle 1. After completion of 9 cycles, patients receive 28-day maintenance cycles with Carfilzomib (days 1, 8, 15) at the maximum tolerated dose (MTD) defined by the Phase I study until disease progression or intolerance. The objectives were to determine the MTD and assess activity and safety. Results As of June 15, 2014, 28 newly diagnosed MM patients were enrolled. Median age was 74 years, 29% of patients were older than 75 years, 36% had ISS stage III, 24% had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. Twelve patients were enrolled in the Phase I portion of the study. At dose level 0 (Carfilzomib 45 mg/m2) no DLT was reported; at dose level 1 (Carfilzomib 56 mg/m2), 1 of 6 patients experienced DLT, consisting of grade 3 creatinine increase; at dose level 2 (Carfilzomib 70 mg/m2) no DLT occurred. The MTD of weekly Carfilzomib was thus established as 70 mg/m2. Toxicity and response data are available for 25 patients, who have completed at least the first cycle; 3 patients are currently receiving their first cycle of treatment. Grade 3-4 drug-related adverse events occurred in less than 15% of patients and included neutropenia (12%, 3 patients), anemia (12%, 3 patients), acute pulmonary edema (8%, 2 patients), pulmonary embolism (4%, 1 patient), creatinine increase (4%, 1 patient), nausea (4%, 1 patient), and fatigue (4%, 1 patient). No peripheral neuropathy was observed. Overall, the wCCd regimen was well tolerated, 3 patients (12%) required Carfilzomib dose reduction (grade 3 creatinine increase, grade 3 transaminase increase and grade 2 fever) and 3 patients (12%) required drug discontinuation due to adverse events (2 acute pulmonary edemas and 1 creatinine increase). Patients received a median of 5 cycles (range 1-9). After 4 induction cycles, 83% of patients achieved at least partial response, 39% at least very good partial response, and 22% complete response. Responses improved over time, as shown in table 1. During the study, only 2 patients progressed and 1 patient died, due to acute pulmonary edema considered probably related to treatment. Conclusions This is the first prospective study evaluating once weekly carfilzomib in treatment-naïve MM. wCCd therapy appears safe and effective in newly diagnosed MM patients. Responses became deeper with subsequent cycles and toxicities were manageable. The response rate observed with weekly carfilzomib compares favorably with similar studies with standard twice weekly carfilzomib infusion. Updated results will be presented at the meeting. Table 1 2nd cycle 4th cycle 6th cycle Complete Response 5% 22% 27% At least Very Good Partial Response 9% 39% 63% At least Partial Response 73% 83% 91% Disclosures Palumbo: Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Off Label Use: Use off-label of Carfilzomib (proteasome inhibitor).. Bringhen:Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria; Onyx: Consultancy. Larocca:Janssen Cilag: Honoraria; Celgene: Honoraria. Cavallo:Onyx: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-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. Gaidano:Onyx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Millenium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Description: Background The current treatment for newly diagnosed elderly multiple myeloma (MM) patients, not eligible for transplant, induces approximately 30% near-complete response/complete response (nCR/CR). Carfilzomib is a novel, irreversible proteasome-inhibitor with significant activity and favourable toxicity profile, including very low rates of peripheral neuropathy and neutropenia. We evaluated efficacy and safety of the combination carfilzomib-cyclophosphamide-dexamethasone (CCd) in elderly newly diagnosed MM patients. Methods The Bryant and Day two-stage design was used to evaluate both efficacy and safety. Patients received oral cyclophosphamide (300 mg/m2 on days 1,8,15), oral dexamethasone (40 mg on days 1, 8, 15, 22) and iv carfilzomib administered over 30 minutes (20 mg/m2 on days 1, 2, and 36 mg/m2 on days 8, 9, 15, 16, cycle 1; 36 mg/m2 on days 1, 2, 8, 9, 15, 16, cycles 2-9) every 28 days for 9 cycles, followed by maintenance with iv carfilzomib (36 mg/m2 on days 1, 2, 15, 16) every 28 days until progression or intolerance. Results Enrollment is complete (58 pts): median age was 71 years, 28% of patients were older than 75 years, 40% had ISS stage III, 35% had unfavorable FISH profile [t(4;14) or t (14;16) or del17p] and 31% are frail, defined according to Charlson co-morbidity index (≥2), geriatric assessment score ADL (

Description: Background: Bendamustine is effective as first-line treatment of multiple myeloma (MM) patients, as well as in heavily pre-treated relapsed/refractory patients. The combination of bendamustine with new drugs has been investigated in patients who have exhausted other treatment options. Aims: This single arm study was conducted, after the approval of our Ethic’s Committee, to assess the activity and safety of bendamustine and dexamethasone in heavily pre-treated relapsed/refractory MM patients in our Home Care Unit program. Patients and Methods: Between May 2012 and March 2013, 8 relapsed/refractory frail MM patients were treated with bendamustine (60 mg/m2 days 1, 8, 15) and dexamethasone (20 mg days 1, 8, 15, 22) for up to nine 28-day cycles. Based on the frailty of our patient’s population, the use of other new agents was avoided. All patients were followed by our Home Care Unit in view of the advanced stage of the disease and of the patients’ inability to attend our day hospital unit. All patients had received a median of 4 (range 2-6) previous lines of therapy including alkylating and new drugs, such as thalidomide (25%), lenalidomide (100%) and bortezomib (100%). One patient received, as salvage treatment, a second autologous stem cell transplant (ASCT) followed by a sibling allogenic transplantation. Six patients (75%) were refractory to bortezomib and 5 (62,5%) to lenalidomide, 4 (50%) were double refractory. Main pre-treatment characteristics were: median time from diagnosis 82.1 months (range 14.2- 255.6), median age 76 years (range 53-83), ECOG performance status 2-3, median Hb level of 10.5 g/dl (range 9.0-13.0), median platelet count of 227.000/mm3 (range 58.000-378.000); all patient had bone lytic lesions and 1 had an extramedullary plasmacytoma of the right thigh; 1 patient had a moderate renal failure (creatinine clearance 44ml/min). Stable disease (SD) was considered a valid therapeutic goal in this advanced cohort of patients. Results: After a median number of 6 cycles administered (range 1-9), among the 7 patients evaluable for response (1 patient was withdrawn early due to death) 75% achieved a clinical benefit (≥ SD) and in particular: 1 very good partial response (VGPR), 3 partial response (PR), 1 minor response (MR) and 1 SD. The patient with extramedullary plasmacytoma had a PR confirmed by the mass reduction. Four patients had an early discontinuation of treatment due to: infections in 3 cases (2 fatal) and a heart failure, not related to treatment, in 1. The median time to best response was 4 months (range 1-6). Median time to progression was 10.8 months (range 5.0-15.2) and the median progression-free survival (PFS) was 9.1 months (range 0.6-15.2). Infectious complication was the primary and major side effect in 6/8 (75%) patients, two of which of grade 5, one grade 3 and three grade 2 according to CTCAE ver. 4. Myelotoxicity was acceptable: only one grade 3-4 anemia, thrombocytopenia and neutropenia. The other non-hematological side effect was nausea in all patients (grade 2), which resolved with antiemetic prophylaxis. Conclusions: Bendamustine and dexamethasone administered at home has proven effective, with a favorable balance in terms of cost/effectiveness, in our cohort of high risk and advanced MM patients in poor clinical conditions. The response rate and PFS are encouraging in this setting of patients and this approach should be considered as a valid option for relapsed/refractory MM, including patients double refractory to lenalidomide and bortezomib. In view of the acceptable and manageable toxicity, this combination is feasible in the framework of a Home Care Unit program. Disclosures Off Label Use: Use off-label of Bendamustine (alkylating). Petrucci:Celgene: Honoraria; Janssen-Cilag: Honoraria; Sanofi: Honoraria; Bristol Meyer-Sqibb: Honoraria.

Description: Key Points This is the first study of carfilzomib-cyclophosphamide-dexamethasone in elderly patients with newly diagnosed multiple myeloma. Carfilzomib-cyclophosphamide-dexamethasone induced high complete response rates and was associated with low toxicity.

Description: Abstract 1882 Poster Board I-905 Introduction. Intracranial involvement (IC) in multiple myeloma (MM) is extremely rare, most frequently resulting from osseous lesions in the cranial vault and skull base. Central nervous system (CNS) MM is even rarer (arising in less than 1% of the patients) consisting in intraparenchymal localizations, cerebral plasmacytomas or CNS myelomatosis. Patients described in the literature are few and treatments are variegate: systemic chemotherapy, (CHT), intrathecal therapy, (IT), radiotherapy, (RT) with results being discouraging with median survivals of 1 month or less. The impact of new drugs (thalidomide, bortezomib, lenalidomide) on CNS and IC MM has not been reported. Patients and Methods. We retrospectively collected clinical and biological data of patients presenting with a CNS or IC MM irrespective of disease status (diagnosis, response, relapse) by sending a questionnaire to the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) centers. Twelve centers answered. Results. Clinical characteristics. A total of 32 patients (M:F=18:14) were registered. All patients had an IC or CNS MM observed in the period between 2004–2009. Ten patients presented a CNS involvement, while 22 had an IC involvement. 9/32 patients had a CNS /IC involvement at diagnosis (4/5); 23/32 patients has a CNS/IC involvement after a median of 16 months (range 1–104) from MM diagnosis. Median age was 63 years (range 44–83) with no difference in both groups; monoclonal protein was IgG 18 (k16, λ2), IgA 6 (k4, λ2), BJ 6 (k3, λ3), non secretory 2. One patient had a solitary primitive IC plasmacytoma, 1 patient had an extramedullary localization in the lung. β2-microglobulin was available in 23 patients with a median value of 4 (range 1.1–17,5): ≤3.5 in 9 patients; 〉3.55.5 in 6 patients. FISH on bone marrow plasma cells was available in 11/32 patients: 60% of the patients showed genomic abnormalities, the more frequent being in order del 13q, t(11;14), del 17p. The most frequent presenting symptoms were in order headache (30%), confusion (27%), visual disturbances (25%), extremities weakness (21%), cranial nerve palsies (21%), paraesthesias (12%), vertigo (5%), convulsions (4%). Magnetic resonance imaging (MRI) of the brain was the preferred radiological imaging in 23/32 patients; computed tomography (CT) was used in 9/32 patients. Cerebrospinal fluid (CSF) involvement was demonstrated in 5/10 CNS MM. Cytogenetic analysis of cerebrospinal fluid was available in two patients who showed a complex karyotype. Treatment. CHT only was administered to 21 patients, CHT+RT to 5 patients, CHT+RT+IT to 3 patients, RT only to 1 , CHT +IT to 1, RT+IT to 1. Bortezomib was used in 15 patients, Thalidomide in 9, Lenalidomide in 3, MP in 7 , VAD in 3, PAD (with liposomal doxorubicin) in 2, cyclophosphamide in 3, other treatments in 3, and 8 patients received an high dose treatment + stem cells transplant (SCT) (5 Autologous/ 3 Allogeneic). 18/32 patients had a response after treatment defined as at least a reduction of 50% of the mass and /or M component (13 CR+VGPR) ; 17 patients had symptoms disappearance. PFS was at a median of 5 months (range 1–36). Median OS for CNS MM was 5 months (range 1–23), OS for IC MM was 9 months (range 1–42). 5/10 patients with CNS MM died at a median of 2 months (1–6); while 13/22 IC MM died at median of 8 months (1–46). 14/32 patients are alive at the present time (5 CNS, 9 IC). Interestingly, of 5 CNS MM patients alive 1 had AutoSCT , 4 received Bortezomib (1 combined with MP, 2 with liposomal doxorubicin, 1 with thalidomide); while of the 9 IC MM alive 3 received Bortezomib, 3 Auto SCT, 1 thalidomide, 1 lenalidomide, 1 cyclophosphamide. β2-microglobulin 〉 5.5 was a poor prognostic factor, as well as age 〉65 years. Conclusions. High dose therapies followed by autologous SCT seem to be the preferable therapy for eligible young patients. Novel drugs such as bortezomib, thalidomide, lenalidomide seem to increase the quality of responses and to prolong survival respect to what reported in the literature. Largest prospective studies are needed to confirm these findings. Disclosures: Petrucci: celgene: Honoraria; Jansenn-cilag: Honoraria. Palumbo:CELGENE: Honoraria.

Description: Background: Solitary plasmacytoma (SP) is a rare form of plasma cell dyscrasia that represents 2.8-5% of all plasma cell disorders. It is characterized by a localized accumulation of neoplastic monoclonal plasma cells, without evidence of systemic disease, such as multiple myeloma (MM). It can be classified into two groups according to the localization: SP of the bone (SBP) and extramedullary plasmacytoma (EMP). The common presentation of the SBP is in the axial skeleton, whereas the EMP is usually seen in the head and neck. The clinical course and prognosis are quite different between these two entities. Here we present the clinical features, treatment strategies and relative prognostic factors of a series of SP patients followed at a single center over four decades. Methods: A retrospective study was carried out in 53 patients with SP referred at our Institution between 1976 and 2012. Patients’ characteristics are shown in Table 1. The median follow-up was 8.9 years (range 0.5-38.1). Thirty-five patients had SBP and 18 patients EMP. The median age was 56.8 years (range 27-80). The male to female ratio was 1.18:1 and 2.6:1 in SBP and EMP, respectively. The vertebral column (48% of cases) and the upper respiratory tract (50% of cases) were the most common sites of involvement SBP and EMP, respectively. Serum M-protein was detected in 62.8% and 27.7% of the SBP and EMP cases (P=0.0156). The tumor sizes were larger in the SBP group than in the EMP group (P=0.0039). Treatment consisted of local radiotherapy (n=26), combined radiotherapy + chemotherapy (n=15), surgery alone (n=4) and chemotherapy alone (n=8). The radiation dose was available for 35 patients and the median radiation dose administered was 41 Gy (range 21-88 Gy). Results: All patients were evaluable for treatment response and outcome. We found no differences between treatment approaches in terms of response rate, progression-free survival (PFS) and overall survival (OS). The local control rate was 94.3% and there was no statistically significant difference between the two groups. Progression to MM was recorded in 20/35 (57.1%) patients with SBP and in 1/18 (5.5%) patients with EMP. The median time to progression was 2.5 years (range 0.6-11). The 5-year PFS rate for all patients was 66.3% (95% CI: 53.9-81.4). Patients with SBP showed a worse PFS rate than EMP patients (53.0% vs 88.5%), with a statistically significant difference (P=0.0003). The total 5-year OS rate was 78.4% (95% CI: 67.3-91.3). Patients with SBP had a significantly worse OS rate than patient with EMP (71.9% vs 88.2%, respectively) (P=0.0290). Univariate analysis revealed that SBP and a larger tumor size (≥5 cm) were adverse prognostic factors affecting PFS (P=0.0027 and P=0.0498, respectively). SBP had an adverse effect also on OS (P=0.0405). In multivariate analysis, bone localization was the only independent worse prognostic factor for both PFS (P=0.0041) and OS (P=0.0216). Conclusions: Patients with SBP have a significantly worse prognosis than patients with EMP, underlining that they are indeed two different entities within the spectrum of plasma cells dyscrasias. The use of modern testing is mandatory to better characterize the patients’ risks of progression and to exclude an occult MM, especially in SBP. There is also a need for further prospective studies with large series of patients evaluating SBP and EMP separately, to elucidate the role of prognostic factors and treatment options for these conditions. Table 1 Characteristics Patient (number) Sex, mean (%) Male Female 33 (62.3)20 (37.7) Age (years) Median (range) ≤ 60 years, mean (%) 56.81 (27-80)33 (62.3) Histological type SBP mean, % EMP mean, % 35 (66)18 (34) Tumor size atDiagnosis, number (%) ≤5 cm 〉5 cm N/A 19 (35.8)20 (37.7)14 (26.5) Serum M protein (%) Positive Negative 27 (50.9)26 (49.1) Urinary B-J protein Positive Negative 6 (11.3)47 (88.7) SBP Anatomic site Vertebral column Long tubal bone Sternum Ribs Craniofacial bone Scapula 17 (48)5 (14)4 (11)3 (8.5)3 (8.5)3 (8.5) EMP Anatomic site Upper respiratory tract Paranasal sinus Lymph nodes GI tract testis 9 (50)4 (22)2 (11)2 (11)1 (6) Disclosures Petrucci: Jansse-Cilag: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria.

Description: Abstract 350 Background. The incorporation of new drugs as induction therapy before autologous transplantation appears to produce a high proportion of complete responses, slightly superior to those achieved by conventional chemotherapy with new drugs. Randomized trials are needed to directly compare current best chemotherapeutic approach with best autologous transplantation strategy. Aims. To compare melphalan, prednisone and lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) in patients younger than 65 years. Methods. As induction, all (N=402) patients received four 28-day cycles of lenalidomide (25 mg days 1-21) and low-dose dexamethasone (40mg days 1,8,15,22) (Rd). Cyclophosphamide (4 g/m2) plus granulocyte-colony stimulating factor was used to mobilize stem cells. As consolidation, patients (N=202) randomized to MPR received six 28-day cycles of melphalan (0.18 mg/kg days 1-4), prednisone (2 mg/kg days 1-4) and lenalidomide (10mg days 1-21); patients (N=200) randomized to MEL200 received tandem melphalan 200 mg/m2 with stem-cell support. All patients were also randomized to receive either aspirin or low-molecular weight heparin (enoxaparin) as thromboprophylaxis. Primary end point was progression-free survival; data were analyzed in intention-to-treat. Results. Patient characteristics were similar in both groups, median age was 58 years. After Rd induction, at least partial response (PR) rate was 84%, at least very good partial response (VGPR) was 32% including 5% complete response (CR). The median yields of CD34+ cells harvested was 10 ×106 CD34+ cells/Kg; 94% of patients collected the minimum dose of 2×106/kg CD34+ cells. After 3 cycles of MPR, at least VGPR rate was 51% and CR 11%. After the first MEL200, at least VGPR rate was 56% and CR 14%. No difference in responses were reported according to cytogenetic abnormalities, such as del13, t(4;14) and t(14;16). After a median follow-up of 12 months, 1-year progression-free survival was 96% for MPR and 94% for MEL200 (p=.92) 1-year overall survival was 98% for MPR and 99% for MEL200 (p=.94). During Rd induction, the most frequent grade 3-4 adverse events were neutropenia (9%), anemia (8%), infections (4%), skin rash (4%), fatigue (2%) and thromboembolic events (1%). During consolidation, the incidence of grade 3-4 neutropenia (97% vs 34%, p