-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

401 Double Autologous Stem Cell Transplantation Significantly Prolongs Progression-Free Survival and Overall Survival in Comparison with Single Autotransplantation in Newly Diagnosed Multiple Myeloma: An Analysis of Phase 3 EMN02/HO95 StudyClinically Relevant Abstract

Clinical Autologous Transplantation: Results
Program: Oral and Poster Abstracts
Type: Oral
Session: 731. Clinical Autologous Transplantation: Results: Novel Conditioning & Maintenance Approaches
Sunday, December 10, 2017: 10:30 AM
Bldg C, Lvl 1, C101 Aud (Georgia World Congress Center)

Michele Cavo, MD1*, Francesca Maria Gay2*, Francesca Patriarca, MD3*, Elena Zamagni, MD4*, Vittorio Montefusco, MD5*, Luca Dozza1*, Monica Galli, MD, PhD6*, Sara Bringhen7*, Nicoletta Testoni, BSc1*, Mariella Grasso, MD8*, Stelvio Ballanti, MD9*, Paola Tacchetti, MD1*, Giampietro Semenzato, MD10*, Anna Marina Liberati11*, Giulia Benevolo12*, Mauro Spriano, MD13*, Paolo Di Bartolomeo, M.D14, Tommaso Caravita di Toritto, MD15*, Angelo D. Palmas, MD16, Anna Maria Cafro, MD17*, Fortunato Morabito, MD18*, Pellegrino Musto, MD19, Rita Rizzi, MD20*, Antonio Palumbo, MD21 and Pieter Sonneveld, MD, PhD22

1Seragnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy
2Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
3Hematology, DAME, University of Udine, Udine, Italy
4Bologna University School of Medicine, Bologna, Italy
5Division of Hematology and Bone MarrowTransplant, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
6Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
7Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy
8Divisione di Ematologia, Ospedale Civico S. Croce e Carle, Cuneo, Italy
9Ospedale S. Maria della Misericordia, University of Perugia, Perugia, Italy
10Department of Medicine, Hematology and Clinical Immunology Section, Padua University School of Medicine, Padova, Italy
11University of Perugia, Azienda Ospedaliera S. Maria, Terni, Italy
12Division of Hematology, AOU Città della Salute e della Scienza, Torino, Italy
13Azienda Ospedaliera Universitaria S. Martino, Genova, Italy
14Department of Hematology, Transfusion Medicine and Biotecnology, " Spirito Santo " Civic Hospital, Pescara, Italy
15Ospedale S.Eugenio Roma, Roma, Italy
16Hematology, Ospedale San Francesco, Nuoro, ITA
17Department of Oncology/Hematology, Niguarda Ca' Granda Hospital, Milan, Italy
18Hematology Unit, Department of Hemato-Oncology, Annunziata Hospital Cosenza, Cosenza, Italy
19IRCCS, Centro Di Riferimento Oncologico Della Basilicata, Rionero in Vulture, Italy
20Medicina Interna e Oncologia Clinica, Policlinico di Bari, Bari, Italy
21University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
22Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands

Background

The role of single vs double autologous stem cell transplantation (ASCT) for newly diagnosed (ND) multiple myeloma (MM) continues to be debated in the novel agent era.

Methods

The phase III EMN02/HO95 study was designed to administer 3-4 cycles of bortezomib-cyclophosphamide-dexamethasone as induction therapy for NDMM and afterwards to randomize eligible patients to receive (randomization 1, R1) standard-dose intensification treatment with bortezomib-melphalan-prednisone (VMP) for four 42-day cycles or high-dose intensification treatment with melphalan at 200 mg/m2 (HDM) plus ASCT. A second randomization to receive or not receive consolidation therapy was planned after the intensification phase, followed by lenalidomide maintenance in both arms. In centers committed to a double ASCT policy, patients were randomized (1:1:1) to receive VMP or single ASCT (ASCT-1) or two sequential courses of HDM (administered 2 to 3 months apart) plus double ASCT (ASCT-2) in order to prospectively compare ASCT-1 vs ASCT-2, which was an additional study objective. For this purpose, and for consistency with the primary study end point, progression-free survival (PFS) from R1 was evaluated.

Results

A total of 1503 patients aged ≤65 years were registered and 1192 were eligible for R1. By study design, 618 patients who received the diagnosis of MM in centers with a double ASCT policy were randomly assigned to VMP (n=203) or ASCT-1 (n=208) or ASCT-2 (n=207). 415 of these patients who were randomized to receive ASCT-1 or ASCT-2 were included in the current pre-specified analysis. Median age was 58 years for patients in the ASCT-1 group and 57 years for those in the ASCT-2 group. The frequency of ISS stage III was 19% in both groups. According to IMWG criteria, a high-risk (HiR) cytogenetic profile defined by t(4;14) ± t(14;16) ± del(17p) positivity (HiR-cyto-3) was detected in 26% and 21% of patients who were evaluable in ASCT-1 (80%) and ASCT-2 (86%) groups. The presence of amp(1q) ± del(1p) ± 1 or more of t(4;14), t(14;16) and del(17p) identified a HiR cytogenetic profile (HiR-cyto-5) which was detected in 55% of patients in ASCT-1 arm and 50% of those in ASCT-2 arm. Median follow-up from R1 was 38 (IQR: 29-47) months for the overall patient population (36 and 39 months for patients randomized to ASCT-1 and ASCT-2, respectively). On an intention-to-treat basis, 3-year estimate of PFS was 73% (95% CI=66-79) for ASCT-2 group vs 64% (CI=57-71) for ASCT-1 group (HR=0.70; CI=0.50-0.98; P=0.040), which represented a 30% reduced risk of progression or death in the ASCT-2 group compared with the ASCT-1 group (Fig. 1a). PFS benefit associated with ASCT-2 was confirmed in subgroups of patients with HiR-cyto-3 (HR=0.42; CI=0.21-0.84; P=0.014), revised ISS (R-ISS) stage II+III (HR=0.64; CI=0.43-0.97; P=0.034), age >55 years (HR=0.64; CI=0.43-0.96; P=0.033); HiR-cyto-5 (HR=0.65; CI=0.42-1.01; P=0.059) and best ≥VGPR (HR=0.64; CI=0.44-0.94; P=0.023). Importantly, ASCT-2 overcame the adverse prognosis conferred by HiR-cyto-3 (3-year PFS: 76% vs 69% for patients with standard-risk cytogenetic profile; P=0.482) (Fig. 1b). In particular, 3-year PFS estimate for patients randomized to ASCT-2 and carrying or lacking del(17p) was 72% vs 73%, respectively (P=0.534). The corresponding PFS values in the ASCT-1 group were 43% vs 67%, respectively (P=0.014). In a multivariate Cox regression analysis, randomization to ASCT-2 (HR=0.65; CI=0.44-0.95; P=0.029), R-ISS I (HR=0.60; CI=037-0.98; P=0.042), absence of HiR-cyto-5 (HR=0.35; CI=0.22-0.55; P<0.001) and best ≥VGPR (HR=0.27; CI=0.17-0.44; P<0.001) were the leading independent predictors of PFS. Overall survival (OS) from R1 was significantly prolonged with ASCT-2 as compared with ASCT-1 (3-year rate: 89% vs 82%; HR=0.52; CI=0.31-0.86; P=0.011) (Fig. 1c), a benefit also seen in subgroups of patients with adverse prognosis, including those with R-ISS stage II+III (HR=0.48; CI=0.27-0.86; P=0.013) and HiR-cyto-5 (HR=0.52; CI=0.28-0.98; P=0.042).

Conclusions

Randomization to ASCT-2 was superior over ASCT-1 in terms of prolonged PFS and OS for the overall patient population and for poor prognosis subgroups of patients with advanced R-ISS disease stage and HiR cytogenetic profile. Incorporation of bortezomib into ASCT-2 abrogated the increased risk of progression or death imparted by t(4;14) ± t(14;16) ± del(17p), and in particular by del(17p) positivity.

Disclosures: Cavo: Janssen: Honoraria; Celgene:: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria. Gay: Amgen: Honoraria; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Roche: 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; Seattle Genetics: 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. Montefusco: Celgena, Janssen: Consultancy, Speakers Bureau. Bringhen: Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Musto: janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria. Palumbo: Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Sonneveld: Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy.

*signifies non-member of ASH