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ABSTRACTIntroduction: Multiple Myeloma (MM) management is rapidly evolving, with a spectrum of novel treatments that have changed our approach to the therapy. Proteasome inhibitors (PIs) have revolutionized the scenario of both relapsed/refractory and newly diagnosed patients. The efficacy of bortezomib, the first PI approved, followed by carfilzomib and, the oral ixazomib, have been tested in several trials as single agents or in combination.Areas covered: In this review, the authors summarize mechanism of action, efficacy and safety of proteasome inhibitors in MM and focus on data derived from clinical trials, analyzing adverse events and their relative management.Expert opinion: The authors believe that, currently, the best course of action in the treatment of MM is to use PIs in combination with immunomodulatory drugs (IMiDs) and/or with monoclonal antibodies for all patients. However, based on the patient-specific characteristics, it is important to avoid inappropriate discontinuation by knowing the single side effects of every agent in order to balance their efficacy and safety.

Background: More than 50% of oncohematological patients suffer from pain syndrome, mostly originating from the bone, which often include nociceptive and neuropathic complaints. Tapentadol, a recently available treatment option for cancer pain, exerts a dual analgesic mechanisms (opioid and noradrenergic), allowing for a high clinical efficacy as well as for a reduction in adverse events compared to traditional opioids. Aim: To explore the safety and efficacy of tapentadol as a suitable agent for the pain management in the setting of oncohematology. Methods: Our observational study included 36 patients with basal pain intensity (NRS) ranging from 5 to 10. Tapentadol prolonged release (PR) was given at the initial dose of 50 mg BID and careful titrated according to the achieved pain control. Results. Tapentadol PR was given at the dosages ranging from 200 and 260 mg/day after a careful titration, allowed for a clinically (-7 points NRS) remarkable reduction of pain intensity without any significant side effects. Conclusion: In oncohematological patients on pain, tapentadol PR was effective and well tolerated, so representing a suitable treatment option in this difficult setting.

Oliva: Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Larocca:Amgen, Celgene, BMS, Janssen-Cilag: Honoraria. Offidani:Janssen: Honoraria; Celgene: Honoraria, Research Funding. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Sanofi, Celgene, Amgen, Janssen, Novartis, Abbivie, BMS: Honoraria; Celgene, Janssen, Amgen, BMS, Mundipharma, Novartis, Sanofi: Research Funding.

Background:The prognostic utility of minimal residual disease (MRD) analysis in multiple myeloma (MM) patients has been well described in the last few years. The role of prolonged maintenance therapy even in persistent MRD negative patients is still unclear. The aim of this study is to evaluate the role of MRD by allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) as predictor of progression-free survival (PFS) in newly diagnosed MM (NDMM) patients receiving Lenalidomide maintenance after frontline treatment.

Foà: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Petrucci: Celgene, Janssen-Cilag, Amgen, Mundipharma, BMS: Honoraria.

Introduction: Among B-lineage ALL, BCR/ABL1-like cases have clearly emerged as a subgroup with peculiar features. By gene expression profiling (GEP), they have a transcriptional signature similar to that of BCR/ABL1+ cases. Moreover, these cases often have IKZF1deletions and CRLF2deregulation, and harbor several lesions involving tyrosine kinases (TKs) that may be patient specific. The incidence varies with age (from 10% of B-lineage ALL in children, to 27% in adolescents/young adults, with a decrease in adults) and they are usually characterized by an inferior outcome, though risk-directed therapy based on minimal residual disease levels has improved prognosis in childhood. Even if GEP promptly recognizes these patients, this technique is expensive, not readily available and not applicable to all centers.

Background:New active classes of drugs such as proteasome inhibitors (e.g., bortezomib) and immunomodulatory drugs-IMiDs (e.g., thalidomide and lenalidomide) are nowadays the standard treatment for multiple myeloma (MM) patients, alone or in association with old agents. The achievement of deeper responses, using novel agents instead of conventional treatment, is a significant prognostic factor for the outcome of these patients, resulting in an improved overall survival (OS) and progression-free survival (PFS). Here, we report the single center real life comparison between the outcome achieved with old agents with that obtained with novel agents in young MM patients treated at first relapse over a 25-year period.

Elderly multiple myeloma (MM) patients are an heterogeneous population. Aging is associated with an increased frequency of co-morbidities, frailty and disability, with negative impact on treatment tolerance and outcome. A simple and reliable scoring system, based on geriatric assessment, has been developed to predict survival and used also to predict the risk of severe toxicities or treatment discontinuation in elderly newly diagnosed MM patients treated with lenalidomide-, bortezomib- or carfilzomib-based induction regimens.Patients with newly diagnosed MM, ineligible for high-dose therapy and autologous stem cell transplantation due to age (≥65 years) or coexisting co-morbidities, enrolled in 3 prospective multicenter trials, were included in the analysis. Up-front dose reductions were performed according to patients age (full doses for patients ≤75 years and reduced for patients >75 years). Details on treatment regimens and results of these studies have previously been reported (Gay F et al EHA 2013, Larocca A et al EHA 2013, Bringhen S et al EHA 2013). At diagnosis, a geriatric assessment had been performed, to assess co-morbidities, cognitive and physical conditions.869 patients were included in the analysis: 659 enrolled in the lenalidomide-based, 152 in the bortezomib-based and 58 in the carfilzomib-based trial. Median age was 74 years, and 44% of patients were older than 75 years. Median follow-up was 18 months.In univariable analysis, the risk of death was higher in patients aged 75-80 (Hazard Ratio, HR 1.37, p=0.11), and in patients older than 80 years (HR 2.75, p<0.001), compared to patients younger than 75 years. Performance status and gender did not significantly impact overall survival (OS). In a multivariable Cox model, an additive scoring system (range 0-5), based on age, co-morbidities, cognitive and physical conditions, was categorized to identify 3 groups: fit (score=0, 39%); unfit (score=1, 31%), and frail (score≥2, 30%). The 18-month OS was 92%, 88% and 73% in the three categories (fit, unfit and frail), respectively.In a Cox's model, including ISS, gender and performance status, the HR compared to the fit category was 1.4 (p=0.18) and 2.9 (p<0.001) in unfit and frail patients. The cumulative 6-month risk of serious adverse events or treatment discontinuation was 44%, 47% and 55% in fit, unfit and frail patients, respectively. The higher mortality rate in unfit and frail patients seems mainly due to higher cumulative incidence of grade ≥3 adverse events (in particular extra hematologic toxicities) causing subsequent treatment discontinuation.The use of a simple scoring system, based on geriatric assessment, allows the identification of groups of patients with different survival and risk of severe toxicities.Larocca: Celgene: Honoraria; Janssen-Cilag: Honoraria. Bringhen:Celgene: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Merck Sharpe & Dohme: Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy. Gay:Celgene: Honoraria; Janssen-Cilag: Honoraria; Celgene: Membership on an entity’s Board of Directors or advisory committees; Byotest: Membership on an entity’s Board of Directors or advisory committees. Boccadoro:Celgene: Research Funding; Janssen-Cilag: Research Funding; Celgene: Consultancy; Janssen-Cilag: Consultancy; Celgene: Membership on an entity’s Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity’s Board of Directors or advisory committees. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

The risk of developing a tumor is 2.1% per year of life in the general population older than 65 years. In MGUS, the incidence of AML/MDS is increased 8 fold compared with normal population, this observation supports a role for non-treatment related factors in the causation of AML/MDS in plasma-cell dyscrasias (Blood, July 27,2011). In multiple myeloma (MM) patients, the risk of second primary malignancy (SPM) is influenced by age and the use of alkylating agents.We examined SPM incidence rates (IRs) per 100 person-years in 2459 newly diagnosed MM patients, enrolled in 9 experimental trials of the European Myeloma Network (RVMM EMN 01, RVMM EMN 441, RVMM PI 026, RVMM PI 302, RVMM PI 209, GIMEMA MM 03 05, GIMEMA MM 04 05, GISMM 2001, HOVON 87). 287 patients received cyclophosphamide-lenalidomide-corticosteroids (CRC), 685 melphalan-prednisone-lenalidomide (MPR), 484 high-dose melphalan followed by lenalidomide maintenance (MEL200-R), 164 melphalan-prednisone (MP), 328 MP-thalidomide (MPT), 257 MP-bortezomib (MPV), 254 MP-bortezomib-thalidomide (VMPT). This post hoc analysis was restricted on pooled data from 1798 patients with at least 1 year of follow-up.As of March 2011 cut-off, median follow-up was 28 months. Median age was 69 years, 49% of patients were aged 65–74 years, and 19% aged ≥75 years. Total cases of SPMs were 30/1798 (IR 0.72), including 8 hematologic (acute leukemia) and 22 solid cancers (gastrointestinal, lung, breast, skin, gynecologic). No cases of SPMs were reported in patients receiving cyclophosphamide and lenalidomide.SPM: second primary malignancy; CRC: cyclophosphamide-lenalidomide-corticosteroids; MPR: melphalan-prednisone-lenalidomide; MEL200-R: high-dose melphalan followed by lenalidomide maintenance; MP: melphalan-prednisone; MPT: MP-thalidomide; MPV: MP-bortezomib; VMPT: MP-bortezomib-thalidomideIn patients receiving lenalidomide and alkylating agents (CRC/MPR/MEL200-R), the cumulative incidence of death for MM and diagnosis of SPMs at 3 years was 13.8% and 2.0%, respectively. In patients not receiving lenalidomide (MP/MPT/MPV/VMPT), the cumulative incidence of death and SPMs at 3 years was 26.1% and 1.1%, respectively. In the analysis restricted to Italian patients treated with lenalidomide and alkylating agents, we report 11 cases of SPMs. This figure is lower than the 15.6 cases expected from the age/sex adjusted incidence derived form the Italian Cancer Registry, with a standardized incidence ratio of 0.70.SPM incidence was lower than expected in all treatment groups. At present, the benefits of continuous therapy with lenalidomide outweigh the potential risk of SPMs. Longer follow-up is needed to definitively assess the risk of SPMs in patients receiving lenalidomide with alkylating agents. With the limitation of a short follow-up, the numbers currently support a role for non-treatment related factors as causes of SPMs. Updated data will be presented at the meeting.Palumbo: 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; Merck: Honoraria; Amgen: Honoraria. Larocca:Janssen-Cilag: Honoraria. Zweegman:Celgene: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding. Musto:Celgene: Consultancy, Honoraria, Research Funding. Lokhorst:Celgene: Consultancy; Genmab: Consultancy. Ria:celgene: Consultancy. Patriarca:Celgene: Honoraria; Schering-Plough: Honoraria. Bringhen:Celgene: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Merck Sharp & Dhome: Membership on an entity's Board of Directors or advisory committees. Hajek:Merk: payment for educational presentation; celgene: Honoraria; Janssen-Cilag: Honoraria. Spencer:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. 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. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees.

Abstract 996

High-dose chemotherapy with haemopoietic stem-cell improves outcome in multiple myeloma (MM). The introduction of novel agents questions the role of autologous stem-cell transplantation (ASCT) in MM patients.In this prospective randomized study, we compared conventional melphalan-prednisone-lenalidomide (MPR) with tandem high-dose melphalan (MEL200) in newly diagnosed MM patients younger than 65 years.All patients (N=402) received four 28-day cycles of lenalidomide (25 mg, d1-21) and low-dose dexamethasone (40 mg, d1, 8, 15, 22) (Rd) as induction. As consolidation, patients were randomized to MPR (N=202) consisting of six 28-day cycles of melphalan (0.18 mg/kg d1-4), prednisone (2 mg/kg d1-4) and lenalidomide (10 mg d1-21); or tandem melphalan 200 mg/m2 MEL200 (N=200) with stem-cell support. All patients enrolled were stratified according to International Staging System (stages 1 and 2 vs. stage 3) and age (<60 vs. ≥60 years). Progression-free survival (PFS) was the primary end point. Data were analyzed in intention-to-treat.Response rates were similar: at least very good partial response (≥VGPR) rate was 60% with MPR vs. 58% with MEL200 (p=.24); the complete response (CR) rate was 20% with MPR vs. 25% with MEL200 (p=.49). After a median follow-up of 26 months, the 2-year PFS was 54% in MPR and 73% in MEL200 (HR=0.51, p<.001). The 2-year overall survival (OS) was similar in the two groups: 87% with MPR and 90% with MEL200 (HR 0.68, p=.19). In a subgroup analysis, MEL200 significantly prolonged PFS in both standard-risk patients without t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 46% in the MPR group vs. 78% in the MEL200 group, HR=0.57, p=.007) and high-risk patients with t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 27% for MPR vs. 71% for MEL200, HR=0.32, p=.004). In patients who achieved CR, the 2-year PFS was 66% for MPR vs. 87% for MEL200 (HR 0.26; p<.001); in those who achieved a partial response (PR), the 2-year PFS was 56% for MPR vs. 77% for MEL200 (HR 0.45; p<.001). In the MPR and MEL200 groups, G3-4 neutropenia was 55% vs. 89% (p<.001); G3-4 infections were 0% vs. 17% (p<.001); G3-4 gastrointestinal toxicity was 0% vs. 21% (p<.001); the incidence of second tumors was 0.5% in MPR patients and 1.5% in MEL200 patients (p=.12). Deep vein thrombosis rate was 2.44% with MPR vs. 1.13% with MEL200 (p=.43).PFS was significantly prolonged in the MEL200 group compared to MPR. This benefit was maintained in the subgroup of patients with standard- or high-risk cytogenetic features. Toxicities were significantly higher in the MEL200 group. This is the first report showing a PFS advantage for ASCT in comparison with conventional therapies including novel agents. These data will be updated at the meeting.Palumbo: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria; Janssen-Cilag: Honoraria. Cavo:celgene: Honoraria. Ria:celgene: Consultancy. Caravita Di Toritto:Celgene: Honoraria, Research Funding. Di Raimondo:celgene: Honoraria. Boccadoro:celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 3069FN2This icon denotes a clinically relevant abstract