Upfront Single Versus Double Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: An Intergroup, Multicenter, Phase III Study of the European Myeloma Network (EMN02/HO95 MM Trial)
Authors: Cavo Michele , Petrucci Maria Teresa , Di Raimondo Francesco , Zamagni Elena , Gamberi Barbara , Crippa Claudia , Marzocchi Giulia , Grasso Mariella , Ballanti Stelvio , Vincelli Donatella Iolanda , Tacchetti Paola , Offidani Massimo , Semenzato Gianpietro , Liberati Anna Marina , Pascarella Anna , Benevolo Giulia , Troia Rossella , Palmas Angelo D. , Cantore Nicola , Rizzi Rita , Morabito Fortunato , Boccadoro Mario , Sonneveld Pieter 
Published: October 2019

Abstract

Background
The role of single vs double autologous stem cell transplantation (ASCT) in patients with newly diagnosed (ND) multiple myeloma (MM) needs to be prospectively investigated in the novel agent era.
Methods
The phase III EMN02/HO95 study was designed to compare (first randomization, R1) (stratification according to ISS stage) standard-dose intensification therapy with bortezomib-melphalan-prednisone (VMP) vs high-dose intensification therapy with melphalan at 200 mg/m2 (HDM) followed by ASCT after 3-4 cycles of bortezomib-cyclophosphamide-dexamethasone as induction therapy. A second randomization to consolidation therapy vs no consolidation was performed after intensification therapy, to be followed by lenalidomide maintenance until progression or toxicity in both arms. A primary study endpoint was progression-free survival (PFS) from R1. In centers with a policy of double ASCT, patients were randomized in a 1:1:1 ratio to either VMP or single ASCT (ASCT-1) or two sequential courses (administered 2 to 3 months apart) of HDM and double ASCT (ASCT-2) in order to prospectively compare ASCT-1 with ASCT-2, which was an additional study objective.
Results
From February 2011 to April 2014, 1510 pts aged ≤65 years with symptomatic NDMM were registered and 1192 of these were eligible for R1. According to the design of the study, 614 eligible patients who received the diagnosis of MM in centers with a double intensification policy were randomly assigned to either VMP (n=199) or ASCT-1 (n=208) or ASCT-2 (n=207). Patients randomized to ASCT-1 or ASCT-2 were included in the current pre-specified analysis. Median age was 59 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 18% and 19%, while revised ISS stage III was 9% and 11%, respectively. Cytogenetic abnormalities were detected by FISH analysis of CD138+ plasma cells. A high-risk (HR) cytogenetic profile, defined by t(4;14) and/or del(17p) and/or t(14;16) (HR cyto-3), was observed in 26% of evaluable patients who were randomized to ASCT-1 and in 21% of those randomly assigned to ASCT-2. If amp(1q) and/or del(1p) were added for the definition of high-risk disease, a HR cytogenetic profile that included at least 1 of the 5 above mentioned chromosomal abnormalities (HR cyto-5) was reported in 55% of evaluable patients in the ASCT-1 group and in 54% of those in the ASCT-2 group. Median follow-up from R1 was 27 (IQR: 20-35) months. On an intention-to-treat basis, the median PFS was 45 months in the ASCT-1 arm and was not yet reached for patients in the ASCT-2 arm; 3-year estimates of PFS were 60% and 73%, respectively (HR=0.66; 95% CI=0.45-0.96; P=0.030). PFS benefit with ASCT-2 was retained across predefined subgroups, including patients with β2-microglobulin >3.5 mg/L (HR=0.59; CI=0.34-0.99; P=0.005), bone marrow plasma cells >60% (HR=0.41; CI=0.22-0.77; P=0.006), LDH values above the upper limits (HR=0.52; CI=0.28-095; P=0.034), revised ISS stage II (HR=0.50; CI=0.31-0.80; p=0.004), HR cyto-3 (HR=0.49; CI=0.24-1.02; P=0.057) and HR cyto-5 (HR=0.57; CI=0.35-0.93; P=0.024). In a multivariate Cox regression analysis stratified by ISS stage, randomization to ASCT-2 (HR=0.62; CI=0.40-0.95; P=0.027) and HR cyto-5 (HR=2.63; CI=1.63-4.16; P<0.001) were the leading independent predictors of PFS. Overall survival was not yet mature and no difference between the two treatment groups was evident.
Conclusions
Upfront double ASCT after bortezomib-based induction therapy for newly diagnosed MM was superior over a single ASCT in terms of prolonged PFS. Clinical benefits of double ASCT were mostly seen in patients with disease-related factors predicting for poor prognosis.

Disclosures
Cavo: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Offidani:Janssen: Honoraria; Celgene: Honoraria, Research Funding. Boccadoro:Janssen: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbivie: Honoraria.