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Background. Proteasome inhibitor (PI)-based induction/consolidation proved to be effective in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for melphalan 200 mg/m2 plus autologous stem-cell transplantation (MEL200-ASCT). High response rates have been reported with carfilzomib (K) plus lenalidomide-dexamethasone (KRd) or cyclophosphamide-dexamethasone (KCd). Lenalidomide (R) alone is a standard of care for post-ASCT maintenance; K maintenance showed promising results in phase I/II studies, but no data on KR maintenance vs R are available. Aims. The aims of this analysis were to evaluate the progression-free survival (PFS) of KRd induction-ASCT-KRd consolidation (KRd_ASCT) vs 12 cycles of KRd (KRd12) vs KCd induction-ASCT-KCd consolidation (KCd_ASCT) and the PFS of KR vs R maintenance. Secondary aims were efficacy in different subgroups of pts and safety of the maintenance phase. Methods. NDMM pts ≤65 years were randomized [R1: 1:1:1, stratification International Staging System (ISS) and age] to: KRd_ASCT: 4 28-day cycles with KRd induction (K 20/36 mg/m2 IV days 1,2,8,9,15,16; R 25 mg days 1-21; dexamethasone [d] 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12: 12 KRd cycles; KCd_ASCT: 4 28-day induction cycles with KCd (K 20/36 mg/m2 IV days 1,2,8,9,15,16; cyclophosphamide 300 mg/m2 days 1,8,15; d 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KCd consolidation cycles. Thereafter, pts were randomized (R2) to maintenance with KR (K 36 mg/m2 days 1,2,15,16, subsequently amended to 70 mg/m2 days 1,15 for up to 2 years; plus R 10 mg days 1-21 every 28 days until progression) or R alone (10 mg days 1-21 every 28 days until progression). Centralized minimal residual disease (MRD) evaluation (8-color second-generation flow cytometry, sensitivity 10-5) was performed in pts achieving ≥very good partial response before maintenance and every 6 months (m) during maintenance. Data cut-off was June 30, 2020. Results. 474 NDMM pts were randomized (KRd_ASCT, n=158; KRd12, n=157; KCd_ASCT, n=159) and analyzed. Pt characteristics were well balanced. Intention-to-treat (ITT) data of pre-maintenance MRD (KRd_ASCT, 62%; KRd12 56%, KCd_ASCT 43%) and safety of the induction/consolidation phases in the 3 arms were already reported (F. Gay et al. ASH 2018; S. Oliva et al. ASH 2019). After a median follow-up from R1 of 45 m, median PFS was not reached with KRd_ASCT, 57 m with KRd12 and 53 m with KCd_ASCT (KRd_ASCT vs KCd_ASCT: HR 0.53, P During maintenance, a similar proportion of pts experienced ≥1 grade (G)3-4 hematologic adverse events (AEs)/serious AEs (SAEs) in the 2 arms (KR 22% vs R 23%); the most frequent were neutropenia (KR 18% vs R 21%) and thrombocytopenia (KR 3% vs R 3%). Rate of ≥1 G3-4 non-hematologic AEs/SAEs was higher with KR (27%) compared with R (15%), P=0.012; the most frequent were infections (KR 4% vs R 7%); all other events were reported in ≤5% of pts and included: gastrointestinal (KR 5% vs R 2%), cardiac (KR 4% vs R 1%), hypertension (KR 3% vs R 0%), and thrombotic microangiopathy (3% vs 0%). 4 pts developed a second primary malignancy in KR (breast 1 pt; thyroid 1 pt; myelodysplastic syndrome 1 pt; non-melanoma skin cancer 1pt) vs 1 pt in R (acute lymphoblastic leukemia). Dose reductions of R were reported in 23% of KR and 29% of R pts; dose reductions of K were reported in 20% of pts. The rate of discontinuation due to AEs was similar in the 2 arms (KR 10% vs R 9%). Conclusions. Treatment with KRd_ASCT significantly improved PFS compared with both KRd12 and KCd_ASCT. Maintenance with KR also improved PFS vs R. Figure Disclosures Gay: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; 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. Musto:Celgene: Honoraria; Amgen: Honoraria. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Belotti:Jannsen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Zamagni:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. De Sabbata:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. D'Agostino:GSK: Membership on an entity's Board of Directors or advisory committees. Liberati:VERASTEM: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; INCYTE: Honoraria; JANSSEN: Honoraria; CELGENE: Honoraria; AMGEN: Honoraria; BMS: Honoraria; BEIGENE: Honoraria; ARCHIGEN: Honoraria; BIOPHARMA: Honoraria; FIBROGEN: Honoraria. Offidani:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau. Boccadoro:AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, lenalidomide and dexamethasone).

We analyzed variations in terms of chromosomal abnormalities (CA) by fluorescence in situ hybridization (FISH) analysis on purified bone marrow plasma cells throughout the progression from monoclonal gammopathy of undetermined significance/smoldering multiple myeloma (MGUS/SMM) to newly diagnosed MM/plasma cell leukemia (NDMM/PCL) at diagnosis and from diagnostic samples to progressive disease. High risk was defined by the presence of at least del(17p), t(4;14), and/or t(14;16). 1p/1q detection (in the standard FISH panel from 2012 onward) was not available for all patients. We analyzed 139 MM/PCL diagnostic samples from 144 patients, with a median follow-up of 71 months: high-risk CA at diagnosis (MGUS/SMM or NDMM) was present in 28% of samples, whereas 37–39% showed high-risk CA at relapse. In 115 patients with NDMM who evolved to relapsed/refractory MM, we identified 3 different populations: (1) 31/115 patients (27%) with gain of new CA (del13, del17p, t(4;14), t(14;16) or 1q CA when available); (2) 10/115 (9%) patients with loss of a previously identified CA; and (3) 74 patients with no changes. The CA gain group showed a median overall survival of 66 months vs. 84 months in the third group (HR 0.56, 95% CI 0.34–0.92, p = 0.023). Clonal evolution occurs as disease progresses after different chemotherapy lines. Patients who acquired high-risk CA had the poorest prognosis. Our findings highlight the importance of performing FISH analysis both at diagnosis and at relapse.

Introduction Flow cytometry is a useful tool for diagnosis and minimal residual disease (MRD) study of hematological diseases. Standard sample preparation protocols are characterized by stain-lyse-wash (SLW). To prevent nonspecific bindings and achieve high sensitivity in MRD studies, lyse-wash-stain-wash (LWSW) is required. To our knowledge, no comparison between the two methods has been performed. Methods We compared mean fluorescence intensity (MFI), stain index, signal-to-noise ratio, and percentage of positive cells of 104 antibodies and of 13 selected antibodies tested in 10 samples simultaneously prepared with the two methods. Results MFI and percentages of positive cells obtained by the two methods did not show significant differences and showed a very high correlation. Stain index and signal-to-noise ratio presented higher values for kappa and lambda surface chains in LWSW samples and a trend of higher values for the other antibodies in SLW samples. Conclusions We suggest to use LWSW method also at diagnosis to obtain more comparable antibody intensity expressions when samples from the same patient are processed for MRD evaluation after bulk lysis. Moreover, LWSW can prevent nonspecific bindings, shows no differences in the identification and quantitation of the populations of interest, and reduces acquisition of cell debris.

Bortezomib-melphalan-prednisone (VMP) and continuous lenalidomide-dexamethasone (Rd) represent the standard treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (MM). To date, no randomized trial has compared VMP to Rd, and there is no evidence of the optimal treatment for newly diagnosed MM, particularly in patients with high-risk cytogenetics [del(17p), t(4;14) or t(14;16)]. We pooled together data from patients with newly diagnosed MM treated with VMP or Rd induction followed by lenalidomide maintenance 10 mg (Rd-R) enrolled in the GIMEMA-MM-03-05 and EMN01 trials, to evaluate the efficacy of these treatments in different subgroups of patients, focusing on those with standard- and high-risk cytogenetics. Overall, 474 patients were analyzed (VMP: 257 patients; Rd-R: 217 patients). No differences in progression-free survival (hazard ratio=0.96) and overall survival (hazard ratio=1.08) were observed between standard-risk patients treated with VMP or Rd-R, whereas among the high-risk patients, the probabilities of progression (hazard ratio=0.54) and death (hazard ratio=0.73) were lower in the patients treated with VMP than in those treated with Rd-R. In particular, standard-risk patients >75 years benefited less from VMP than from Rd-R (hazard ratio for progression-free survival=0.96; hazard ratio for overall survival=1.81). In this non-randomized analysis, VMP and Rd-R were equally effective in younger (≤75 years), standard-risk patients, while older ones (>75 years) benefited more from Rd-R. In high-risk patients, VMP improved progression-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196).

Maintenance demonstrated to improve survival in newly diagnosed multiple myeloma (NDMM) patients and the achievement of complete response (CR) is a strong predictor of survival. Nevertheless, the role of maintenance according to response after induction/consolidation has not been investigated so far. To evaluate the impact of maintenance according to response, we pooled together and retrospectively analyzed data from 955 NDMM patients enrolled in two trials (GIMEMA-MM-03-05 and RV-MM-PI-209). Primary endpoints were progression-free survival (PFS)1, PFS2 and overall survival (OS) of CR patients randomized to maintenance and no maintenance. Secondary endpoints were PFS1, PFS2 and OS in very good partial response/partial response (VGPR/PR) patients. Overall, 213 patients obtained CR after induction/consolidation, 118 received maintenance and 95 no maintenance. In patients achieving CR, maintenance significantly improved PFS1 (HR 0.50, P

INTRODUCTION Post-transplant cyclophosphamide (PTCY) has expanded the application of haploidentical stem cell transplantation (haplo-HSCT). Thymic function may play a pivotal role in long-term clinical outcomes. OBJECTIVES To evaluate the kinetics of long-term immune thymus-dependent reconstitution after PTCY haplo-HSCT. METHODS Twenty-nine patients (median age 53) underwent T-cell replete haplo-HSCT with PTCY. Blood samples were collected before conditioning and at 1, 3, 6, 12, 18, 24 months after transplantation. Analyses of CD4 and CD8 T-cell subsets by flow-cytometry were correlated by generalized linear models with Real-Time PCR quantification of signal joint T-cell receptor excision DNA circles (sjTRECs), specific marker of naive T-cells thymopoiesis. A) Naive; b) central; c) memory; and d) revertant CD4 and CD8 T-cells were defined as follows: a) CD45RA+CD62L+; b) CD45RO+CD62L+; c) CD45RO+CD27-; and d) CD45RA+/45RO+, respectively. SjTRECs real-time PCR was performed on genomic DNA (100 ng) extracted from sorted CD4 and CD8 T-cells. RESULTS Following PTCY induced T-cell depletion, a constant gradual increase in absolute numbers of all CD4 and CD8 T cell subsets and of sjTRECs copies from the first month up to two years post-transplant was observed (Figure 1). Overall, at two years, CD4 and CD8 T-cell levels and sjTRECs levels were however lower than those observed in healthy donors. sjTRECs kinetics was associated with the increase in naive T-cells (overall, p CONCLUSIONS Active thymic function despite age-dependent involution, substantially contributes to T-cell reconstitution after haplo-HSCT. Chronic GVHD and older age are however significantly correlated with lower thymic activity. Overall, lower production of sjTRECs after haplo-HSCT as compared after HLA identical sibling HSCT may partly be due to a higher degree of “mismatching” of MHC molecules during thymic re-education.

L’emoglobinuria parossistica notturna (EPN) e un disordine ematologico raro caratterizzato da anemia emolitica, trombosi e difetti dell’ematopoiesi. Tale patologia e dovuta a una mutazione somatica del gene PIG-A che comporta la mancata produzione del glicosil-fosfatidil-inositolo (GPI), a cui si ancorano proteine di membrana quali CD55 e CD59 che inibiscono l’attivazione del complemento su diversi tipi cellulari. Dal 2010 il nostro Laboratorio partecipa alla compilazione dell’archivio CLONEPnh. Integrando i dati in esso inseriti con quelli contenuti nell’archivio del nostro Laboratorio e stato valutato il cambiamento negli anni del numero di richieste di ricerca del clone EPN e, in relazione a esso, come e variato il numero dei nuovi cloni individuati. E stata effettuata un’analisi citofluorimetrica a sei colori su sangue periferico, di pazienti afferenti alla Divisione Universitaria di Ematologia dell’Azienda Ospedaliera Citta della Salute e della Scienza di Torino, utilizzando il FLAER (tossina batterica inattivata) e i seguenti anticorpi: CD45, CD14, CD33, CD66, CD55, CD59, CD235a. I campioni sono stati acquisiti con citofluorimetro FACSCantoII e analizzati con il software FACS Diva. I dati sono stati inseriti nell’archivio CLONEPnh ( www.CLONEPnh.com ). Dai dati inseriti nell’archivio CLONEPnh si evince che le richieste di ricerca di EPN sono state 13 nel 2010, 16 nel 2011, 28 nel 2012 e 12 nei primi sei mesi del 2013 e i cloni individuati sono stati, rispettivamente, 1, 0, 1 e 1. Un andamento simile, anche se con un numero decisamente minore di analisi richieste, e stato riscontrato anche negli anni precedenti (dal 2000) analizzando l’archivio del nostro Laboratorio. I nostri dati mostrano un aumento negli anni di analisi effettuate, a cui, pero, non e corrisposto un aumento dei cloni individuati. L’aumento delle richieste si puo giustificare considerando che la diagnosi di EPN e diventata prevalentemente citofluorimetrica e che le recenti linee guida consigliano, in pazienti con displasie midollari, di ricercare e monitorare cloni di modesta entita mediante la metodica ad alta sensibilita. Tuttavia, per ridurre il costo in termini di tempo e risorse, sarebbero auspicabili l’elaborazione e la validazione di protocolli citofluorimetrici piu rapidi con l’utilizzo di un pannello ridotto di reagenti.

Introduction Several trials have shown that maintenance therapy prolongs progression-free survival (PFS) in multiple myeloma (MM) patients, eligible and ineligible for autologous stem cell transplantation (ASCT); conflicting data exist about its impact on overall survival (OS). The role of maintenance in patients with a sensitive disease is still unclear. We conducted a retrospective pooled analysis to clarify the impact of continuous treatment in patients achieving a complete response (CR). Methods Data from newly diagnosed MM patientsenrolled in 4 phase III trials were analysed. Two trials included ASCT-eligible patients: RV-MM-209 [melphalan-prednisone-lenalidomide (MPR) vs melphalan 200 mg/m2 (Mel200), followed by lenalidomide maintenance vs no maintenance), RV-MM-EMN-441 (cyclophosphamide-lenalidomide-dexamethasone vs Mel200, followed by lenalidomide vs lenalidomide-prednisone maintenance). Two studies enrolled elderly, ASCT-ineligible patients: GIMEMA-MM0305 (bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide vs bortezomib-melphalan-prednisone) and EMN01 (MPR vs cyclophosphamide-prednisone-lenalidomide vs lenalidomide-dexamethasone, followed by lenalidomide vs lenalidomide-prednisone maintenance). The primary endpoint of the study was to evaluate the impact of maintenance on PFS and OS in patients who achieved CR. Univariate analyses of OS and PFS were performed. Response was considered as a time-dependent variable with a landmark point at 12 months. Lastly, a multivariate analysis was performed to evaluate the impact of maintenance and ASCT as independent variables. Results A total of 1964 patients were retrospectively analysed. Of 1503 patients who received maintenance therapy, 254 achieved a CR and 931 a very good partial response (VGPR) or partial response (PR). After a median follow-up of 41 months, a significant 5-year OS (80% vs 54%; HR 0.55, p=0.02; Figure 1) and 5-year PFS (52% vs 19%; HR 0.47, p The same analysis was conducted in patients achieving a suboptimal response (VGPR or PR): the 5-year PFS advantage was confirmed in patients who received maintenance vs patients who did not (30% vs 13% HR 0.65, p A subgroup analysis was conducted in CR patients according to the treatment received [ASCT vs conventional chemotherapy (CC)]; the PFS benefit among patients treated with maintenance was confirmed across both the subgroups (ASCT group: HR 0.45, p=0.02; CC group: HR 0.45 P In multivariate analysis, maintenance therapy and treatment with ASCT confirmed the favourable impact on PFS and OS in patients achieving CR. Conclusion In CR patients,maintenance therapy significantly prolongs PFS and OS. In order to optimize treatment efficacy and to prolong survival in patients with a sensitive disease, the intensification with maintenance is strongly recommended. Disclosures Off Label Use: Use off-label of drugs for the dose and/or schedule and/or association. Gay:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gaidano:Novartis: Honoraria, Other: Advisory boards; Celgene: Research Funding; Karyopharm: Honoraria, Other: Advisory boards; Roche: Honoraria, Other: Advisory boards; Morphosys: Honoraria, Other: Advisory boards; GlaxoSmithKline: Honoraria, Other: Advisory boards; Amgen: Honoraria, Other: Advisory boards; Janssen: Honoraria, Other: Advisory boards. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Patriarca:Janssen-Cilag, Celgene, Merck Sharp & Dohme: Honoraria. Di Raimondo:Janssen-Cilag, Celgene: Honoraria. Hájek:Janssen-Cilag: Honoraria; Celgene, Merck Sharp & Dohme: Consultancy, Honoraria. 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. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.

Introduction : Cytogenetic abnormalities by fluorescence in situ hybridization (FISH) are clinically relevant prognostic factors in MM. Data in transplant ineligible patients treated with bortezomib or lenalidomide in first-line therapy for high-risk (HiR) patients is limited. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. This sub-analysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible patients with newly diagnosed MM (NDMM) treated with bortezomib-based induction (BORT) or lenalidomide-based (LEN) treatment. Methods : In the GIMEMA-MM-03-05-trial, patients were randomized to bortezomib-melphalan-prednisone-thalidomide for 9 cycles followed by maintenance with bortezomib-thalidomide (VMPT-VT) vs VMP for 9 cycles, without maintenance. In the EMN01-trial, patients were randomized to melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd) for 9 cycles, followed by maintenance with lenalidomide alone or plus prednisone continuously. Results of these studies have previously been reported (Palumbo A et al JCO 2010 and 2014; Magarotto V et al Blood 2016 127(9)). Cytogenetics were assessed using FISH. Patients were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. HiR cytogenetics included del(17p), t(4;14), and t(14;16); all other patients were categorized as standard risk (StR). Subgroup analyses were performed to determine the consistency of treatment effects of BOR vs LEN in the different subgroups using interaction terms between treatment and FISH, ISS, age, sex, Karnofsky PS and LDH. The different effect of BORT vs LEN in cytogenetic subgroups was confirmed by one sensitivity analysis where the follow-up of the BORT study was reduced to make the follow-up times similar; and by another sensitivity analysis with multiple imputation method for missing cytogenetic value. Results : 902 of 1165 patients from the intent-to-treat population had available cytogenetic profiles, with 243 (27%) patients in the HiR group and 659 (73%) in the StR group. In the BORT vs LEN groups, median age was 71 vs 73 years (p In the subgroup analysis, a significant difference was found in the cytogenetic subgroup with a superior advantage of BORT versus LEN in HiR group, whereas no significant difference was found between BORT and LEN in the other subgroups analyzed (ISS, age, sex, Karnofsky PS and LDH) (interaction-p=0.01) (Fig. 1 B). BORT treatment resulted in a reduced risk of death or progression compared with LEN in patients with HiR. In HiR patients, median PFS was 30.8 with BORT compared with 14.8 months with LEN (HR: 0.54; 95% CI: 0.41-0.72); in StR, median PFS was 29.1 with BORT compared with 22.1 months with LEN (HR: 0.87; 95%; CI: 0.72-1.05) (Fig. 1 A). Considering the standard of care VMP and Rd, in the HiR group (n=95) VMP resulted in a 48% reduced risk of death or progression compared with Rd (HR: 0.53; 95% CI: 0.34-0.83), whereas no significant difference in PFS was found in the StR group (n=273) (HR: 1.00; 95% CI: 0.75-1.33), interaction-p=0.02. BORT treatment resulted in a reduced risk of death in patients with HiR cytogenetics: median OS was 62.4 months with BORT compared with 43.2 months with LEN (HR: 0.68; 95% CI: 0.47-0.96); in StR, median OS was 78.1 months with BORT and was not reached with LEN (HR: 1.06; 95% CI: 0.82-1.36), interaction-p=0.04 (Fig. 1 A). In patients with del(17p) (n=131) median PFS was 18.0 vs 12.9 months for BORT vs LEN (HR: 0.71; 95% CI: 0.49-1.04), interaction-p=0.73. In patients with t(4;14) (n=118) median PFS was 31.5 vs 15.2 months for BORT vs LEN (HR: 0.41; 95% CI: 0.27-0.62) interaction-p=0.002. In patients with t(14;16) (n=31) median PFS was 36.2 vs 9.8 months for BORT vs LEN treated patients (HR: 0.34; 95% CI: 0.16-0.76), interaction-p=0.045. Conclusions : BORT treatment resulted in a PFS and OS benefit vs LEN in patients with HiR cytogenetics. Treatment with VMP led to a significant reduction of the risk of death or progression vs Rd in HiR patients. These results support VMP induction as a standard treatment option for patients with NDMM who are ineligible for transplant with HiR cytogenetics. Disclosures Larocca: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. 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: Janssen: Honoraria; Celgene: Honoraria. Patriarca: MSD Italia: Honoraria; Janssen: Honoraria. Corradini: Gilead: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Bosi: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Petrucci: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Boccadoro: Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria.

Introduction: High throughput techniques, such as massively parallel sequencing, are becoming an attractive approach to characterize multiple myeloma (MM) genomic profiles. However, the clinical relevance and contribution to risk assessment of such approaches need to be established. The Multiple Myeloma Research Foundation (MMRF)CoMMpass trial (NCT01454297) has collected data from 1000 newly-diagnosed MM patients enrolled worldwide and observed through an expected follow-up of up to eight-years. Comprehensive analysis of somatic mutations detected in purified MM cells could reveal disease features with prognostic value, which may not have been detected using traditional approaches. Materials and methods: We analyzed data from the interim analysis 8 cohort. CD138+ purified MM specimens from bone marrow aspirates and mononuclear cells from peripheral blood were collected at diagnosis. Whole exome libraries from both tumor and constitutional DNA samples were created. Somatic single nucleotide variants (SNV) were identified using three different variant callers (Seurat,Strelka andMutect), only nonsynonymous SNV calls made from at least two callers were included in the analysis. Patients were analyzed on an intention-to-treat basis. We evaluated the impact on progression free survival (PFS) of recurrently mutated genes (with at least a nonsynonymous SNV in more than 10 patients) in a Cox model adjusted for international staging system (ISS) and cytogenetic profile (high risk, standard risk and missing). An additive score related to mutated genes was calculated on the basis the level of each coefficient estimated using a Cox Model with backward selection based on theAkaikeInformation Criterion (AIC). Results: 517 patients with baseline somatic mutation data were included in the analysis. Median age at diagnosis was 64 years (range 27-93). All patients received novel agents as first line treatment; 236 (45.6%) received autologous stem cell transplantation (ASCT). Each patient showed a median number of 55 nonsynonymous somatic SNV (range 8-1970) in a median number of 47 genes (range 5-1741). Excluding immunoglobulin genes, the most recurrent mutated genes were KRAS (25%), NRAS (19.5%), TTN (12.1%), MUC16 (9.1%) and DIS3 (9.1%). Based on the results of a multivariable Cox model corrected for ISS and cytogeneticprofile, we created a scoring system determined by the mutational status of 9 genes identified in a nonbiased manner (Table 1). Three groups were identified: group I (score 0-2, 17%); group II (score=3, 51%), and group III (score >3, 32%). After a median follow-up of 371 days, the 18-month PFS rate was 93% for group I, 85% for group II, and 67% for group III. In a Cox model adjusted for ISS and cytogeneticprofile, the hazard ratio was 2.34 (p=0.112) for group II versus group I, and 5.96 (p Conclusion: The use of a prognostic model based on the mutational status of 9 recurrently mutated genes could improve risk assessment of newly-diagnosed MM patients. To our knowledge, this is the largest study correlating nonsynonymous somatic SNV with MM patients' outcome. Longer follow-up and validation in independent cohorts are needed to confirm our findings. Disclosures Larocca: Amgen, Celgene, BMS, Janssen-Cilag: Honoraria. Gay:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria.

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 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 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 Conclusion. These results demonstrate that 1. both once-weekly and twice-weekly schedules in combination with MP ± thalidomide are highly effective in patients ≥ 65 years; 2. once-weekly schedule significantly reduced the incidence of PN and decreased the rate of discontinuation, resulting in similar cumulative bortezomib doses in the two groups; 3. the improvement in the safety profile was not associated with any reduction in the efficacy. Disclosures: Bringhen: Celgene: Honoraria; Janssen Cilag: Honoraria. Leoni: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. Elice:Celgene: Honoraria; Novatis: 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. 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.