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The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study.

Background. Iberdomide is a novel oral cereblon E3 ligase modulator (CELMoD TM) with enhanced direct antitumor effects and immune stimulatory effects, compared to lenalidomide or pomalidomide. In the ongoing phase 1/2 CC-220-MM-001 study, iberdomide plus dexamethasone had a favorable safety profile and demonstrated clinically meaningful activity in triple-class refractory multiple myeloma (MM) patients, including those refractory to lenalidomide and pomalidomide (IMiDs ®). Based on these data, we aimed to evaluate the safety and clinical activity of 3 different doses of iberdomide as a novel maintenance treatment post-transplant in newly diagnosed MM patients. Here we report results from the first interim analysis for patients who have been treated with at least 6 treatment cycles, or discontinued treatment earlier.

According to 2021 ESMO guidelines, treatment of newly diagnosed (ND) transplant eligible (TE) Multiple Myeloma (MM) patients is settled by an induction phase followed by single or tandem autologous stem cell transplantation (ASCT) and Lenalidomide (Len) maintenance. Len maintenance was approved in Italy in May 2018 due to the results of the meta-analysis by McCarthy et al. of three large randomized clinical trials. Before the approval of daratumumab-bortezomib-thalidomide-dexamethasone (D-VTD) regimen, VTD triplet combination was the most used induction regimen across Italian centers. In addition, given the data from the EMN02 trial, in the last years tandem ASCT has been a consolidated practice especially for high-risk cytogenetic patients. However, only a minority of patients enrolled in the meta-analysis of McCarthy received VTD induction and in most of them a single ASCT has been performed.

A sequential approach including bortezomib induction, intermediate-dose melphalan, and autologous stem cell transplantation (ASCT), followed by lenalidomide consolidation-maintenance, has been evaluated. Efficacy and safety data have been analyzed on intention-to-treat and results updated. Newly diagnosed myeloma patients 65 to 75 years of age (n = 102) received 4 cycles of bortezomib-pegylated liposomal doxorubicin-dexamethasone, tandem melphalan (100 mg/m2) followed by ASCT (MEL100-ASCT), 4 cycles of lenalidomide-prednisone consolidation (LP), and lenalidomide maintenance (L) until disease progression. The complete response (CR) rate was 33% after MEL100-ASCT, 48% after LP and 53% after L maintenance. After a median follow-up of 66 months, median time-to-progression (TTP) was 55 months and median progression-free survival 48 months. Median overall survival (OS) was not reached, 5-year OS was 63%. In CR patients, median TTP was 70 months and 5-year OS was 83%. Median survival from relapse was 28 months. Death related to adverse events (AEs) occurred in 8/102 patients during induction or transplantation. Rate of death related to AEs was higher in patients ≥70 years compared with younger (5/26 vs 3/76, P = .024). Bortezomib-induction followed by ASCT and lenalidomide consolidation-maintenance is a valuable option for elderly myeloma patients, with the greatest benefit in those younger than 70 years of age.

A sequential approach including bortezomib induction, intermediate-dose melphalan, and autologous stem cell transplantation (ASCT), followed by lenalidomide consolidation-maintenance, has been evaluated. Efficacy and safety data have been analyzed on intention-to-treat and results updated. Newly diagnosed myeloma patients 65 to 75 years of age (n = 102) received 4 cycles of bortezomib-pegylated liposomal doxorubicin-dexamethasone, tandem melphalan (100 mg/m2) followed by ASCT (MEL100-ASCT), 4 cycles of lenalidomide-prednisone consolidation (LP), and lenalidomide maintenance (L) until disease progression. The complete response (CR) rate was 33% after MEL100-ASCT, 48% after LP and 53% after L maintenance. After a median follow-up of 66 months, median time-to-progression (TTP) was 55 months and median progression-free survival 48 months. Median overall survival (OS) was not reached, 5-year OS was 63%. In CR patients, median TTP was 70 months and 5-year OS was 83%. Median survival from relapse was 28 months. Death related to adverse events (AEs) occurred in 8/102 patients during induction or transplantation. Rate of death related to AEs was higher in patients ≥70 years compared with younger (5/26 vs 3/76, P= .024). Bortezomib-induction followed by ASCT and lenalidomide consolidation-maintenance is a valuable option for elderly myeloma patients, with the greatest benefit in those younger than 70 years of age.

Thalidomide plus dexamethasone (TD) is a standard induction therapy for myeloma. We aimed to assess the efficacy and safety of addition of bortezomib to TD (VTD) versus TD alone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma.

In multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination, bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2 on days 1 through 5 and prednisone at 60 mg/m2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5 patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.

In multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination, bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2on days 1 through 5 and prednisone at 60 mg/m2on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5 patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.

Mina: Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:GSK: Honoraria; 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Corradini:KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria. Liberati:CELGENE: Honoraria; BIOPHARMA: Honoraria; ARCHIGEN: Honoraria; BEIGENE: Honoraria; BMS: Honoraria; AMGEN: Honoraria; FIBROGEN: Honoraria; INCYTE: Honoraria; 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; JANSSEN: Honoraria. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Bringhen:Takeda: Consultancy; 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; Bristol-Myers Squibb: Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including ixazomib, dexamethasone, cyclophosphamide, thalidomide and bendamustine).

INTRODUCTION.The proteasome inhibitor (PI) Ixazomib, approved for the treatment of relapsed/refractory multiple myeloma (MM), represents an appealing option for the management of elderly patients, due to its oral administration and the lack of peripheral neuropathy. We previously presented preliminary results of the phase II EMN10-Unito study investigating Ixazomib in combination with dexamethasone (Id), Cyclophosphamide-dexamethasone (ICd), Thalidomide-dexamethasone (ITd) or Bendamustine-dexamethasone (IBd) as induction therapy followed by single-agent Ixazomib maintenance in transplant-ineligible newly diagnosed (ND) MM patients. Here we present updated results of the study with a longer follow-up.

Background.In multiple myeloma (MM), the role of minimal residual disease (MRD) by multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) is well established (H. Avet-Loiseau et al. IMW 2019, S. Oliva et al. EHA 2020).

INTRODUCTION.Bortezomib- and/or lenalidomide-based combinations are standard initial approaches in transplant (ASCT) ineligible NDMM. Different studies confirmed the advantages of continuous treatment. Despite the benefits of bortezomib maintenance, the parenteral administration and the risk of peripheral neuropathy (PN) limit its long-term use. The oral proteasome inhibitor (PI) Ixazomib plus Lenalidomide-dexamethasone was effective and well tolerated at diagnosis or relapse. The need for a convenient and well tolerated PI-based frontline therapy for an extended duration with minimal cumulative toxicity remains an unmet need for the elderly. In this prospective, multicenter, phase II randomized study, we assessed Ixazomib in combination with dexamethasone, Cyclophosphamide, Thalidomide or Bendamustine, followed by Ixazomib maintenance in ASCT-ineligible NDMM.

Background.High rates of response and minimal residual disease (MRD) negativity have been reported with the use of novel treatment options in multiple myeloma (MM) patients (pts) eligible for autologous stem-cell transplantation (ASCT). Despite very promising results, there is still a proportion of pts who do not respond to therapy or relapse early. This represents an unmet medical need.

Larocca: Amgen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Corradini:Servier: Honoraria; Amgen: Honoraria; Gilead: Honoraria, Other: Travel Costs; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; KiowaKirin: Honoraria; Jazz Pharmaceutics: Honoraria; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Celgene: Honoraria, Other: Travel Costs. Mina:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Liberati:Bristol-Myers Squibb: Honoraria; Roche: Other: Clinical trial support; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Honoraria, Other: Clinical trial support; Novartis: Other: Clinical trial support. Petrucci:Takeda: 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; 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Patriarca:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. 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. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Cellini:Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Janssen: Honoraria. Galli:Takeda: Honoraria; Leadiant (Sigma-Tau): Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Aquino:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. De Sabbata:Janssen: 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. Ballanti:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Offidani:Janssen: 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; Amgen: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Bringhen:Celgene Corporation: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria.The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma.

Gay: Takeda: 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; 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; 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: 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. Offidani:Bristol-Myers Squibb: 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; Takeda: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vozella:Celgene: Honoraria; Amgen: Honoraria. Belotti:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Galli:Takeda: Honoraria; Leadiant (Sigma-Tau): Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Gozzetti:Celgene: Honoraria; Amgen: Honoraria; Jansenn: Honoraria; BMS: Honoraria. Giuliani:Janssen: Research Funding. Musto:Amgen: Honoraria; Celgene: Honoraria. Cavo:sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding.The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma.

Gay: Roche: Other: Advisory Board; Seattle Genetics: Other: Advisory Board; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria; Takeda: Honoraria, Other: Advisory Board. Galli:Sigma-Tau: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Belotti:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board. Zamagni:BMS: 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; Takeda: 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. Angelucci:Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol in MDS; Celgene: Honoraria, Other: Chair DMC proptocol BELIEVE 1 and BELIVE 2 in Thalassemia; Vertex Pharmaceuticals Incorporated (MA) and CRISPR Therapeutics AG (CH): Other: Chair DMC CRISPR CAS9 in Hemoglobinopathies; Jazz Pharmaceuticals Italy: Other: Local (national) advisory board on AML; Roche Italia: Other: Local (national) advisory board on biosimilars. Annibali:Celgene; Takeda; Amgen, Janssen Cilag: Honoraria. Offidani:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. Palumbo:Takeda: Employment. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cavo:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: 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; Adaptive Biotechnologies: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria.

Tacchetti: Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria. Zamagni: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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: 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. Bringhen:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy. Offidani:Celgene: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Montefusco:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board. Cavo:Amgen: 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, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: 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; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Larocca: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria. De Paoli:Amgen: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Other: Advisory Board; Gilead: Other: Advisory Board. Galli:Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Sigma-Tau: Honoraria. Montefusco:Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Caravita di Toritto:Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Amgen: Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Takeda: Other: Advisory Board; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding. Giuliani:Celgene Italy: Other: Avisory Board, Research Funding; Takeda Pharmaceutical Co: Research Funding; Janssen Pharmaceutica: Other: Avisory Board, Research Funding. Patriarca:Jazz: Other: Travel, accommodations, expenses; Janssen: Other: Advisory role; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; MSD Italy: Other: Advisory Role. Offidani:Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. Cavo:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: 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, Research Funding, Speakers Bureau; Bristol-Myers Squibb: 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. Palumbo:Takeda: Employment. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding. Bringhen:Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria.

INTRODUCTION: Elderly patients with newly diagnosed multiple myeloma (NDMM) are highly heterogeneous and their outcome is influenced by many factors: beside age, also comorbidities, general physical fitness, and cognitive function play a crucial role. The IMWG frailty score combines age, functional status, and comorbidities, and it identifies fit, intermediate-fit and frail patients, with different risk of toxicity, treatment discontinuation, and mortality (Palumbo A et al. Blood 2015). Until now, evidence-based tailored treatments according to patients' frailty are still lacking. Therefore, this phase III study investigated the efficacy and feasibility of dose/schedule-adjusted lenalidomide-dexamethasone therapy followed by lenalidomide maintenance (Rd-R) versus continuous lenalidomide-dexamethasone (Rd) in elderly, intermediate-fit NDMM patients.

Introduction:The phase 3 GIMEMA-MMY-3006 trial comparing bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (MM) provided the first demonstration of increased CR rate, the primary study endpoint, and prolonged PFS with VTD (Cavo M et al, Lancet 2010). However, updating trial results with longer follow-up than earlier reported is needed to assess the effects of treatment interventions on OS and to identify factors predicting for favorable long term outcomes.

Background:Proteasome inhibitor (PI)-based induction and consolidation proved to be effective in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for melphalan 200 mg/m2-autologous stem cell transplant (MEL200-ASCT). High response rates have been reported with the second-generation PI Carfilzomib in combination with Lenalidomide-dexamethasone (KRd) or Cyclophosphamide-dexamethasone (KCd).

Background:The pattern of multiple myeloma (MM) relapses includes both biochemical relapses, characterized by the increase of monoclonal paraprotein in absence of organ dysfunction and CRAB symptoms, and clinical relapses, when the increase of monoclonal protein is associated with organ dysfunction. The International Myeloma Working Group (IMWG) recommends starting the subsequent treatment when either clinical relapse or a significant paraprotein increase occur (Rajkumar S. V. et al., Blood2011 Feb 3; 1sted.). To date, no data are available about the benefit of treatment at biochemical relapse rather than waiting for clinical relapse. Data from the RETRIEVE study suggested that re-treatment with bortezomib is safe and effective (Petrucci M. T. et al., Haematologica2010; 95 (s2):152). Here we report the results of a phase II multi-center, randomized study that investigated the efficacy and safety of bortezomib re-treatment at biochemical relapse compared to observation until clinical relapse.

BACKGROUND.The genomic heterogeneity that characterizes all Multiple Myeloma (MM) patients (pts) is the consequence of an evolutionary process operating during the pre-neoplastic phase of the disease. Whatever genomic event occurs, it accounts for the de-regulated expression of either one of the cyclin D or other key regulators of cell cycle progression. Therefore, a deficient regulation of cell cycle control is considered as a hallmark of MM. Moreover, among the MM genomic heterogeneity, several lesions are recurrent and their presence significantly impacts the prognosis.

Gay: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Sanofi: 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. Petrucci:Celgene: Honoraria; Janssen-Cilag: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Di Raimondo:Janssen-Cilag, Celgene: Honoraria. Caravita:Celgene: Honoraria. Ria:Italfarmaco: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Bringhen:Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag, Celgene, Novartis: Honoraria; Onyx: Consultancy. Patriarca:Janssen-Cilag, Celgene, Merck Sharp & Dohme: Honoraria. Spencer:Celgene: Honoraria. Hajek:Merck Sharp & Dohme: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Celgene: 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.

Off Label Use: lenalidomide used as off-label. Ferrero:MUNDIPHARMA: Honoraria. Gay:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Patriarca:Merck Sharp & Dohme: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Petrucci:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria; SANOFI: Honoraria; BRISTOL MYERS SQUIBB: Honoraria. Caravita:Celgene: Honoraria. Di Raimondo:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Musto:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. 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. Palumbo:Array BioPharma: Honoraria; 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; Amgen: Consultancy, Honoraria; Sanofi: Honoraria.

Background.Minimal residual disease (MRD) detection by multi-parameter flow cytometry (MFC) and real time quantitative PCR (RQ-PCR) is highly predictive of outcome in multiple myeloma (MM) patients (pts). Less is known on the ability of maintenance therapy to modulate MRD levels. The primary end-point of this study was to monitor MRD during maintenance therapy and to evaluate the impact on outcome.

Cavo: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Tacchetti:Janssen and Celgene: Honoraria. Zamagni:Celgene: Honoraria; Janssen-Cilag: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Brioli:Celgene: Honoraria.

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 quality of response and the residual disease after treatment are important prognostic factors in several hematological diseases including multiple myeloma (MM). Several papers demonstrated that the deeper the response after treatment, the longer the survival. However few data are available on the monitoring of minimal residual disease (MRD) during the maintenance therapy in transplant eligible MM patients.to evaluate the role of maintenance therapy in reducing MRD and the role of monitoring the response to predict clinical relapse.newly diagnosed MM patients enrolled in the RV-MM-EMN-441 trial (NCT01091831) and achieving at least a very good partial response (VGPR) after consolidation were included in the study. Patients received 4 Lenalidomide-Dexamethasone (RD) courses as induction, Cyclophosphamide to mobilize bone marrow stem cells (BMSC) and then were randomized to receive 6 cycles of Cyclophosphamide-Lenalidomide-Dexamethasone (CRD) or Autologous Stem Cell Transplantation (ASCT) with Melphalan 200 mg/m2. All patients received maintenance therapy with Lenalidomide (R) or Lenalidomide-Dexamethasone (RD) until relapse. MRD analysis was performed in a single laboratory (University of Turin, Italy) using flow cytometry according to European Myeloma Network guideline (Rawstron AC, Haematologica 2008). Samples of bone marrow (BM) were collected at diagnosis, after consolidation, after 3 and 6 courses of maintenance and then every 6 months until clinical relapse. The samples were considered MRD +ve if ≥ 0.01% of PC were detected. Immunophenotypic (IF) relapse was defined as an increase of ≥ 25% in the amount of malignant plasma cells in BM compared to the previous determination.Fifty patients (27 female/23 male) with a median age of 57 yrs (40-65) entered the study. According to ISS, 27 patients were stage I, 15 stage II and 8 stage III. Fish risk profile was standard in 31 patients, high in 11 and not available in 8. Twenty-five patients received CRD as consolidation and 25 underwent ASCT. The median follow-up was 28.6 months. After consolidation 16 (32%) patients achieve a complete response (CR) and 34 (68%) a VGPR. MRD was negative in 19/48 (40%) patients, of which 12 received ASCT (out of 23, 52%) and 7 received CRD (out of 25, 28%). Patients receiving ASCT showed a lower value of residual cells (median 0.08%, range 0 – 1.00) compared to patients receiving CRD (median 0.5%, range 0 – 2.9%, p=0.0134). The lower MRD value was achieved after consolidation in 31 patients (62%), after 3 courses of maintenance in 6 patients (12%) and after 6 or more courses of maintenance in 13 patients (26%). The increase in quality of response was observed primarily in patients receiving CRD: the average amount of residual plasma cells in bone marrow was 71/uL after induction, lowering to 51/uL after 6 and 12 courses of maintenance therapy. Nine patients clinically relapsed after an average time of 25.6 months from the beginning of the therapy and in all patients this was anticipated by immunophenotypic relapse.1) consolidation therapy with ASCT determines a deeper response compared to CRD; 2) maintenance therapy can improve the quality of response, in particular in patients not receiving ASCT; 3) Immunophenotypic relapse anticipate the clinical relapse. These results suggest the possible role of MRD monitoring to better assess the response to therapy also during maintenance and as marker of early relapse.Ladetto: Celgene: Research Funding, Speakers Bureau; Janssen Cilag: Research Funding, Speakers Bureau; Mundipharma: Research Funding, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. 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:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

The quality of response and the residual disease after treatment are important prognostic factors in several hematological diseases including multiple myeloma (MM). Several papers demonstrated that the deeper the response after treatment, the longer the survival. However few data are available on the monitoring of minimal residual disease (MRD) during the maintenance therapy in transplant eligible MM patients.

Abstract 4210This icon denotes a clinically relevant abstract

Cavo: Janssen, Celgene, Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Di Raimondo:Celgene, Janssen: Honoraria, Speakers Bureau. Offidani:Janssen, Celgene: Honoraria. Caravita:Celgene, Janssen, Novartis, Genzyme: Honoraria. Boccadoro:Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

In a randomized phase 3 study, the use of VTD as induction therapy prior to and consolidation therapy following double ASCT increased the rate of complete or near complete response (CR/nCR) and extended PFS in comparison with TD given as induction and post-ASCT consolidation therapy in 474 newly diagnosed MM patients (Cavo et al, Lancet 2010). However, the specific impact of VTD consolidation on improved clinical outcomes was not defined.To address this issue, we performed a per-protocol analysis of 321 patients who received the entire treatment program, including the two pre-planned cycles of consolidation therapy with either VTD (160 of 236 patients, 68%) or TD (161 of 238 patients, 68%). By study design, two 35-d cycles of VTD (V 1.3 mg/m2 on days 1, 8, 15, and 22; T 100 mg/d on days 1–35; D 40 mg on the days of and after each V administration) or TD (at the same doses as in VTD) were given as consolidation therapy to patients randomly assigned to each of the two respective induction regimens. Patient and disease characteristics at baseline were comparable in the two groups of patients.The rates of CR and CR/nCR were significantly higher after consolidation therapy with VTD compared with TD (CR: 61% vs 47%; p=0.012; CR/nCR: 73% vs 61%; p=0.020). The impact of VTD consolidation on post-ASCT enhanced rates of CR and CR/nCR was confirmed by the McNemar test (CR: p=0.0009; CR/nCR: p=0.004) which conversely failed to demonstrate a significant increase in the frequencies of CR (p=0.052) and CR/nCR (p=0.110) with TD consolidation therapy. The absolute probability of upgrading from less than CR before consolidation to CR after consolidation was 31% with VTD and 17% with TD (Pearson chi-square test: p=0.03). Ninety six percent of patients who upgraded from less than CR to CR after VTD consolidation were in nCR (44%) or VGPR (52%) before starting consolidation therapy. A landmark analysis (with the landmark set as the start of consolidation therapy) was performed to compare time to progression (TTP), PFS, and overall survival (OS) between treatment groups. With a median follow-up of 30 months, the estimated 3-year probability of relapse or progression was 38% with VTD and 52% with TD (p=0.039 by Kaplan-Meier analysis) (HR: 0.68, 95% CI: 0.47–0.98, p=0.041). PFS was significantly longer for patients receiving VTD consolidation than for those treated with TD (3-year estimates: 62% vs 46%; p=0.025) (HR: 0.66, 95% CI: 0.46–0.95, p=0.027), a gain particularly evident for patients who failed to achieve CR after ASCT (3-year PFS estimates: 66% vs 43%; HR: 0.54, 95% CI: 0.32–0.91, p=0.022). Superior PFS with VTD vs TD consolidation was retained across poor prognosis subgroups, including patients with t(4;14) and/or del(17q) (HR: 0.44, p=0.004), del(13q) (HR: 0.44, p=0.002), β2-microglobulin >3.5 mg/L (HR: 0.57, p=0.025), lactate dehydrogenase >190 U/L (HR: 0.57, p=0.005), or ISS stage 2 and 3 (HR: 0.57, p=0.021). In a multivariate regression analysis, the most important and independent variables positively correlated with PFS were VTD consolidation therapy (p=0.002), double ASCT (p=0.001), low β2-microglobulin (p<0.0001), and absence of t(4;14) and/or del(17q) (p<0.0001). No OS difference was seen between the two groups. Both VTD and TD consolidation therapy were very well tolerated. The frequency of treatment-emergent grade 3–4 adverse events was comparable in the two groups (9.3% in VTD, 8.6% in TD). Of particular note, peripheral neuropathy was 0.6% with VTD, while the rates of skin rash and deep vein thrombosis were 0.6% in each of the two groups. Patients treated with VTD received 93% of planned doses of bortezomib and thalidomide.In comparison with TD, post-ASCT consolidation therapy with the triplet VTD regimen significantly increased the rates of CR and CR/nCR, and extended landmarked TTP and PFS. Superior PFS with VTD consolidation was maintained across poor prognosis subgroups, including those with advanced ISS stage and/or high-risk cytogenetic profiles. In a multivariate regression analysis VTD consolidation was confirmed to be an independent variable favorably affecting PFS. The superior activity seen with VTD versus TD as induction therapy before ASCT was retained despite the same triplet regimen being used as post-ASCT consolidation.Cavo: Millennium: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Genzyme: Honoraria. Off Label Use: Bortezomib and Thalidomide as post autotransplantation consolidation therapy in myeloma. Patriarca:Schering-Plough: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Roche: Honoraria. Petrucci:Celgene: Honoraria; Janssen: Honoraria. Di Raimondo:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Palumbo:Merck: Honoraria; 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. Offidani:Celgene: Honoraria; Janssen: Honoraria. Baccarani:Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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

Abstract 1871

Newly diagnosed myeloma (MM) patients who receive thalidomide-based regimens have a high risk of thromboembolic events. Preliminary studies on MM patients receiving a combination of lenalidomide (R) and dexamethasone have shown an increased incidence of thrombosis as well, with a calculated odds ratio of about 3.5 of developing thrombosis.In a prospective, multicenter phase III trial (RV-MM-PI-209) newly diagnosed patients were treated with lenalidomide and low-dose dexamethasone (Rd) induction and subsequently randomized to receive consolidation with lenalidomide + melphalan + prednisone (MPR) or high dose melphalan (MEL200). In this sub-study we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) as anticoagulant prophylaxis during Rd induction and MPR consolidation. End-points were incidence of venous thromboembolism (VTE), acute cardiovascular events, sudden death, major and minor bleeding.402 newly diagnosed MM patients were enrolled in the randomized trial RV-MM-PI-209. Treatment schedule included four 28 day cycles of lenalidomide (25 mg days 1–21) and low-dose dexamethasone (40 mg days 1,8,15,22) (Rd) as induction. As consolidation, patients were randomized to receive six 28-day cycles of melphalan (0.18 mg/kg days 1–4), prednisone (2 mg/kg days 1–4) and lenalidomide (10 mg days 1–21) (MPR, N=202) or tandem melphalan 200 mg/m2 with stem-cell support (MEL200, N=200). All eligible patients were randomly assigned to receive LMWH (Enoxaparin 40 mg/d, N=166) or ASA (Aspirin 100 mg/d, N=176) for the duration of the induction therapy and for consolidation therapy in the MPR group; 60 patients were excluded from this sub-study because of indication for anticoagulant/antiplatelet therapy or high-risk of bleeding.Patient characteristics and distribution of major risk factors were similar in the two groups. At the time of the present analysis 381 and 130 patients are evaluable during Rd induction and consolidation respectively. During the induction phase, the overall incidence of any grade 3–4 thrombotic events was 1% in the LMWH group, 2,4% in the ASA group (p=.45). VTE, mostly of the lower limbs were equally distributed in the two groups (1%; p not significant), while pulmonary embolism was observed only in the ASA group (2%; p not significant). Median time to onset of thrombotic events for patients who received LMWH or ASA were 2.1 and 1 months, respectively. No acute cardiovascular events were observed and only minor bleeding was detected in the LMWH group (1%). During consolidation no thrombotic events were observed in the MPR group, only one central venous catheter thrombosis was observed in the MEL200 group.The overall incidence of thrombotic events was less than 5% in all groups and confirmed the safety of low dose dexamethasone in association with Lenalidomide. No significant benefit was seen with LMWH over ASA in this patient population. LMWH and ASA are likely to be effective thromboprophylactic regimens in lenalidomide treated patients with newly diagnosed multiple myeloma. The analysis will be updated for the meeting.Cavallo: CELGENE: Honoraria. Guglielmelli:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Boccadoro:CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; JANSSEN-CILAG: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. 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.

Abstract 1092

GVHD is a major complication after allogeneic stem cell transplantation (HSCT). The median incidence of grade II-IV acute(a)GVHD is about 40%, depending on several risk factors, whereas chronic(c)GVHD occurs in more than 50% of long term survivors after HSCT.Histopathology has a critical role in obtaining diagnosis and comprehending pathophysiology of GVHD. However, clinical or technical factors may hamper histological interpretation. Aim of the present retrospective study was to optimize the role of histopathology in the management of GVHD. Recommendations of Pathology Working Group (National Institutes of Health Consensus, ASBMT, BBMT 2006) were matched with clinical-laboratory data in order to test histological sensitivity, specificity and positive predictive value (PPV).One hundred sixty consecutive bioptical samples were performed in 68 adult patients with suggestive signs or symptoms of organ involving a/c GVHD (n=137) or as screening test in asymptomatic patients (n=23),who underwent allogeneic HSCT at our institution between Jul 1999 and Feb 2009.Median age at transplant was 50 ys (range 17-70),with a median follow-up 32 mo (3-111). Diagnoses were 89/160 acute and 16/160 chronic leukemia, 16 lymphomas, and 39 myelomas. Sixteen % of biopsies were taken from MUD transplanted patients. The source of stem cells was bone marrow in 88/160 (median TNC 2.9 × 108/Kg, range 1.11-5.60), and peripheral blood in 72 (median CD34+cells 5.87 × 106/Kg, range 1.17-10.15). The biopsies, were collected from organ presenting clinical signs suggestive of GVHD involvement. If more organs were simultaneously involved,the one with more severe symptoms was selected. The biopsies were performed early at the onset of the clinical manifestations, and before modification of immunosuppressive (IS) therapy. A specific form containing the main clinical data (time from transplant, type of conditioning and possible differential diagnosis) accompanied the specimens. The histopathological diagnosis was guaranteed within 24-48 hours from the collection. The 160 bioptical samples were collected from the skin (n=86), gastrointestinal tract (GI) (oral mucosa n=5, stomach n=40, or colon n=24), liver (n=4), lung (n=1).Median time from HSCT to biopsy was 968 days (range 76-3341).PPV for the following variables was calculated: conditioning therapy (reduced intensity versus standard), source of stem cell (BM versus PB),type of organ involved (skin, versus upper GI tract, versus lower GI tract), time from HSCT to biopsy (<=180 vs >180 dy) and concomitant IS at the time of biopsy.Seventy out of 157 biopsies were negative, 9/157 suggestive for GVHD, 48/157 were diagnostic for acute GVHD (33 had histological grade <= 2, 15 > 2), and 30/157 for chronic GVHD. The sensitivity of the histopathological test was 79% in the whole group, whereas the specificity was 80%. PPV was 86%, negative predictive value was 71%. About the analyzed variables,the following had a PPV >=90% :RIC conditioning (90%),PB source (93%),samples collected from GI tract (upper tract 90%, lower 100%),time to biopsy >180 dy(90%) and absence of concomitant IS treatment (90%).The biopsies performed as screening test in asymptomatic patients had a sensitivity of 100% but a specificity of 83%, and the true positive are as frequent as the false positive results. Conclusions: clinical data identified at the time of sampling (RIC conditioning, PBSC transplants, lower GI tract, time to biopsy >180 dy and absence of concomitant IS) may improve the power of histology. Moreover, despite of a low number of specimens, the biopsies performed as screening test seem to have no critical role in decision making.No relevant conflicts of interest to declare.

A phase III study of melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) incorporating thalidomide (T) and dexamethasone (D) with or without the addition of bortezomib (V) as first-line therapy for younger (≤65 years) patients (pts) with newly diagnosed multiple myeloma (MM) is currently being conducted by the Italian Myeloma Network GIMEMA.By study design, pts were random assigned to receive three 21-d cycles of either bortezomib-thalidomide-dexamethasone (VTD) (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or thalidomide-dexamethasone (TD) (both drugs at the same dose and schedule than in VTD) as induction therapy in preparation for ASCTs. Two 35-d cycles of either VTD or TD were given as consolidation therapy following ASCTs (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle). Primary study end point was the rate of high-quality responses [immunofixation negative complete response (CR) and ≥very good partial response (VGPR)] to induction therapy. Secondary study end points included response to, and toxicity of, subsequent treatment phases (including first and second ASCTs, and consolidation therapy), progression-free survival (PFS) and overall survival (OS). Analyses were intent to treat. All the 474 pts were evaluated for response to, and toxicity of, induction therapy. Responses reported by study investigators were centrally reassessed to confirm CR and VGPR; pts reported as complete responders but in whom bone marrow aspirate was not evaluable or not performed were reassessed as in VGPR. The VGPR category included the subcategories of near CR and VGPR.The study was closed to pts accrual after a total of 480 pts were enrolled; of these, 6 failed inclusion criteria and the remaining 474 were randomized to the VTD (n=236) or TD (n=238) arm. The mean total dose of V received in induction therapy was 14.7 mg (or 94% of that planned). Grade 3 peripheral neuropathy (PN) and skin rash (SR) were reported more frequently with VTD induction therapy than with TD (PN: 9.7% vs 2.1%, respectively; P<0.001) (SR: 10% vs 1.7%, respectively; P<0.001). In the VTD arm, resolution or reduction to at least grade 2 of PN was observed within a median of 26 days. Remarkably, once-weekly standard dose administration of V and reduction of T dose in VTD as consolidation therapy resulted in a dramatic decrease in the frequency of grade ≥3 PN (2%) and SR (1%). Reported rates of herpes zoster infection with VTD as both induction and consolidation therapy were 0.4% and 1%, respectively. Overall, the CR (≥VGPR) rate with VTD induction therapy was 19% (62%) vs 5% (31%) with TD (P<0.001 for both CR and ≥VGPR comparisons); no pt had disease progression while on VTD, as compared to 5% of pts treated with TD (P<0.001) who discontinued therapy and went off study. Progression through the subsequent treatment phases was associated with an increase in the frequency of CR and ≥VGPR up to a final value of 44% and 80%, respectively, in the VTD arm; the corresponding rates in the TD arm were 32% (p=0.02) and 65% (p=0.001), respectively. On an intention to treat basis, best responses in the VTD vs TD arm were the following: CR, 55% vs 38%, respectively (P<0.001); ≥VGPR: 87% vs 69%, respectively (P<0.001). Superiority of the VTD vs TD arm in terms of CR rate was confirmed in pts with high-risk cytogenetics, as defined by the presence of t(4;14) and/or del(17p) (58% vs 33%, respectively; p=0.004). Two year-projected PFS was 85% in the VTD arm as compared to 75% in TD (p=0.008). Improved PFS with VTD vs TD, both added to double ASCT, was consistent across subgroup analyses of pts with poor prognosis, including those with high-risk cytogenetic profiles (p=0.03; HR=0.42, 95% CI: 0.18 to 0.96). PFS curves for pts in the VTD arm who carried or not high-risk cytogenetics were similar (p=0.19). No difference in OS was seen between the two treatment groups, but longer follow up is required.Incorporation of VTD into double ASCT for newly diagnosed MM resulted in a significant improvement in clinical outcomes (CR, ≥VGPR, PFS) in comparison with TD and double autotransplantation. Superior benefit with VTD and double ASCT in comparison with the control group was maintained in pts at high risk of progression or death, including those with t(4;14) and/or del(17p).Cavo: Celgene: Honoraria; Ortho Biotech, Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Honoraria; Novartis: Honoraria.

The risk of venous thromboembolism (VTE) is high in newly diagnosed myeloma (MM) patients who receive thalidomide-based regimens. Anticoagulant prophylaxis is recommended. Controversies exist on the best thromboprophylactic regimen to adopt. Aims. In this prospective, multicenter phase III trial we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) or low-fixed dose warfarin (WAR) as anticoagulant prophylaxis. End-points were incidence of VTE, acute cardiovascular events, sudden death, major and minor bleeding.In a GIMEMA study, 991 newly diagnosed MM patients were randomized to VTD (Velcade 1.3 mg/m2 d 1,4,8,11; Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or TD (Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or VMPT (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4; Talidomide 50 mg/d) or VMP (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4). In a sub-study, patients treated with VTD or TD or VMPT were randomly assigned to receive LMWH (Enoxaparin 40 mg/d, N=223) or ASA (Aspirin 100 mg/d, N=227) or WAR (Warfarin 1.25 mg/d, N=223) for the duration of the induction therapy; 61 patients were excluded from sub-study because of indication for anticoagulant/antiplatelet therapy or high-risk of bleeding. Patients treated with VMP (N=257) did not receive any prophylaxis and were used as controls.Patient characteristics and distribution of major risk factors were similar in all groups. The incidence of VTE was 5% in the LMWH group, 6% in the ASA group and 8% in the WAR group (p not significant). VTEs were 2% in the VMP group. Median time to onset of VTE for patients who received LMWH or ASA or WAR were 4.7, 2.4 and 2.4 months, respectively. Patients who received higher doses of both steroids and thalidomide (VTD and TD) had a higher VTE incidence (7%) in comparison with those who received lower doses (VMPT, 3%, p=0.06). Patients treated with bortezomib (VTD and VMPT) had a lower VTE incidence (5%) in comparison with patients on TD (8%, p=0.08). The rates of cardiovascular events were 2% in the LMWH group, 1% in the ASA group and 0.5% in the WAR group. The incidence of major and minor bleeding was 2% in the LMWH group, 3% in the ASA group and 1% in the WAR group (p not significant). The incidence of combined thrombosis, bleeding and cardiovascular events was 9% in the LMWH group, 10% in the ASA group and 9% in the WAR group (p not significant).The overall incidence of VTE was less than 10% in all groups and was not superior to that expected during the natural course of MM. The LMWH patients had lower risk of VTE, although no statistical difference was observed. LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens. The final analysis on 991 patients will be presented at the meeting.No relevant conflicts of interest to declare.

Abstract 492

Abstract 351This icon denotes an abstract that is clinically relevant.

Abstract 4647

Over the last few years, Thalidomide-Dexamethsone (TD) has been one of the most commonly used induction regimens for the treatment of newly diagnosed multiple myeloma (MM). In a phase III study conducted by the Italian Myeloma Network GIMEMA, TD was compared with Velcade-Thalidomide-Dexamethasone (VTD) as induction therapy in preparation for, and as consolidation after, melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) in pts aged ≤65 years with symptomatic MM. Up-front VTD comprised Velcade, 1.3 mg/m2 on d 1, 4, 8, and 11; Dexamethasone, 40 mg on each day of and after Velcade administration; Thalidomide, 200 mg/d through d 1 to 63. Pts randomized to TD received Thalidomide as in VTD and Dexamethasone, 40 mg/d on d 1–4 and 9–12 of every cycle. Primary study end point was the rate of complete response (CR)/near CR (nCR) following three 21-d cycles of induction therapy. The study was started in May 2006 and was closed to accrual in April 2008, after a total of 480 pts were enrolled. Of these, 399 pts (199 randomized to VTD and 200 to TD) could be evaluated for primary study end point and toxicity of induction regimens (secondary end point). All analyses were intent to treat. In comparison with TD, VTD effected significantly higher rates of response (≥partial response: 78.5% vs 92%, P<0.001), including CR (6% vs 21%, P<0.001), CR+nCR (12% vs 33%, P<0.001) and ≥very good partial response (VGPR) (30% vs 61%, P<0.001). Remarkably, no pt treated on VTD had disease progression, as compared to 4.5% of pts on TD (P=0.002). Serious adverse events were recorded in 13.5% of pts randomized to VTD vs 12.5% of those assigned to TD. Although grade ≥3 peripheral neuropathy (PN) and skin rash (SR) were more frequent with VTD than TD (PN: 9% vs 2.5% of pts, P=0.005) (SR: 7.5% vs 1% of pts, P=0.001), only 4 pts in the VTD arm (2 in each of the two toxicity sub-groups) necessitated early treatment discontinuation. Overall, discontinuation of primary therapy due to treatment-related adverse events was required in 4.5% of pts on VTD vs 5% of those on TD, including a single pt in VTD and 2 pts in TD who died early. Eight additional pts randomized to TD discontinued induction therapy and went off study due to disease progression. Peripheral blood stem-cell (PBSC) harvest and response to first ASCT (secondary study end points) could be assessed in 297 pts (145 randomized to VTD and 152 to TD) for whom data were available at the time of analysis. Pts who achieved the minimum threshold dose of CD34+ cells to safely perform double ASCT (≥4×106/kg) were 91% in the VTD arm vs 87% in TD; median yields were 9.3 and 10.6 (×106 CD34+ cells/Kg), respectively. Pts who actually received the first ASCT were 89% (129/145) in VTD and 80% (121/152) in TD. On an intention-to-treat basis, the rates of high-quality responses in the VTD arm were significantly higher than in TD, including CR (41% vs 20%, P<0.001), CR+nCR (54% vs 29%, P<0.001) and ≥VGPR (75% vs 53%, P<0.001). After a median follow-up of 15 months, progression-free survival (PFS) was significantly superior with VTD as compared to TD (20-month estimate: 93% vs 86%, P=0.04), while the 20-month overall survival rate was 93% for both treatment groups. We conclude that, in comparison with TD, three 21-d cycles of VTD as primary therapy for newly diagnosed MM significantly increased the CR+nCR rates, up to values previously seen with one or two autotransplants preceded by conventional chemotherapy. Importantly, response benefit with up-front VTD vs TD translated into significantly higher CR+nCR rates after ASCT and significantly improved PFS. Effective combinations of novel induction agents, such as VTD, can, thus, have a remarkable impact on both pre and post-ASCT clinical outcome. Updated results, including response to second ASCT and consolidation therapy, will be presented at the meeting.

Over the last few years, Thalidomide-Dexamethsone (TD) has been one of the most commonly used induction regimens for the treatment of newly diagnosed multiple myeloma (MM). In a phase III study conducted by the Italian Myeloma Network GIMEMA, TD was compared with Velcade-Thalidomide-Dexamethasone (VTD) as induction therapy in preparation for, and as consolidation after, melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) in pts aged ≤65 years with symptomatic MM. Up-front VTD comprised Velcade, 1.3 mg/m2on d 1, 4, 8, and 11; Dexamethasone, 40 mg on each day of and after Velcade administration; Thalidomide, 200 mg/d through d 1 to 63. Pts randomized to TD received Thalidomide as in VTD and Dexamethasone, 40 mg/d on d 1–4 and 9–12 of every cycle. Primary study end point was the rate of complete response (CR)/near CR (nCR) following three 21-d cycles of induction therapy. The study was started in May 2006 and was closed to accrual in April 2008, after a total of 480 pts were enrolled. Of these, 399 pts (199 randomized to VTD and 200 to TD) could be evaluated for primary study end point and toxicity of induction regimens (secondary end point). All analyses were intent to treat. In comparison with TD, VTD effected significantly higher rates of response (≥partial response: 78.5% vs 92%, P<0.001), including CR (6% vs 21%, P<0.001), CR+nCR (12% vs 33%, P<0.001) and ≥very good partial response (VGPR) (30% vs 61%, P<0.001). Remarkably, no pt treated on VTD had disease progression, as compared to 4.5% of pts on TD (P=0.002). Serious adverse events were recorded in 13.5% of pts randomized to VTD vs 12.5% of those assigned to TD. Although grade ≥3 peripheral neuropathy (PN) and skin rash (SR) were more frequent with VTD than TD (PN: 9% vs 2.5% of pts, P=0.005) (SR: 7.5% vs 1% of pts, P=0.001), only 4 pts in the VTD arm (2 in each of the two toxicity sub-groups) necessitated early treatment discontinuation. Overall, discontinuation of primary therapy due to treatment-related adverse events was required in 4.5% of pts on VTD vs 5% of those on TD, including a single pt in VTD and 2 pts in TD who died early. Eight additional pts randomized to TD discontinued induction therapy and went off study due to disease progression. Peripheral blood stem-cell (PBSC) harvest and response to first ASCT (secondary study end points) could be assessed in 297 pts (145 randomized to VTD and 152 to TD) for whom data were available at the time of analysis. Pts who achieved the minimum threshold dose of CD34+cells to safely perform double ASCT (≥4×106/kg) were 91% in the VTD arm vs 87% in TD; median yields were 9.3 and 10.6 (×106CD34+cells/Kg), respectively. Pts who actually received the first ASCT were 89% (129/145) in VTD and 80% (121/152) in TD. On an intention-to-treat basis, the rates of high-quality responses in the VTD arm were significantly higher than in TD, including CR (41% vs 20%, P<0.001), CR+nCR (54% vs 29%, P<0.001) and ≥VGPR (75% vs 53%, P<0.001). After a median follow-up of 15 months, progression-free survival (PFS) was significantly superior with VTD as compared to TD (20-month estimate: 93% vs 86%, P=0.04), while the 20-month overall survival rate was 93% for both treatment groups. We conclude that, in comparison with TD, three 21-d cycles of VTD as primary therapy for newly diagnosed MM significantly increased the CR+nCR rates, up to values previously seen with one or two autotransplants preceded by conventional chemotherapy. Importantly, response benefit with up-front VTD vs TD translated into significantly higher CR+nCR rates after ASCT and significantly improved PFS. Effective combinations of novel induction agents, such as VTD, can, thus, have a remarkable impact on both pre and post-ASCT clinical outcome. Updated results, including response to second ASCT and consolidation therapy, will be presented at the meeting.