MEETING NEWS MYELOMA
Doubling Down on Double Transplant for Myeloma : Updated Results from EMN02 / H095
More than a year ago , at the 2016 ASH Annual Meeting , Michele Cavo , MD , from the Serágnoli Institute of Hematology at Bologna University School of Medicine in Italy , presented preliminary results from the phase III EMN02 / H095 trial , which found that following bortezomibbased induction therapy , double autologous hematopoietic cell transplantation ( AHCT ) led to longer progression-free survival ( PFS ) than single AHCT in patients with newly diagnosed multiple myeloma ( MM ). At the 2017 ASH Annual Meeting , Dr . Cavo presented updated results , which confirmed the previous findings and revealed an overall survival ( OS ) benefit with double AHCT .
This intergroup , multicenter study enrolled 695 patients with newly diagnosed , symptomatic MM ( median age = 58 years ; range = 18-64 years ) between February 2011 and April 2014 . A total of 415 patients were eligible for analysis at the time of data cutoff ( date not provided ).
All 1,503 participants were initially treated with standard dose-intensification therapy ( bortezomib , melphalan , prednisone ; VMP ); 1,192 were then randomized to receive standard-dose intensification therapy with VMP for four 42-day cycles or highdose – intensification therapy ( melphalan 200 mg / m 2 ; HDM ) plus AHCT . A second randomization assigned people to receive either single AHCT ( n = 208 ) or double AHCT ( n = 207 ). The second AHCT occurred within 60 days of the first , and patients received two sequential courses of HDM , administered two to three months apart .
Post-AHCT , patients received lenalidomide maintenance therapy until disease progression .
Median follow-up from first randomization was 38 months ( range = 29-47 months ); for patients in the single- and double-AHCT groups , median follow-up was 36 and 39 months , respectively ( ranges not provided ). Patient characteristics were similar between the two study arms . The frequency of International Staging System ( ISS ) stage III was 19 percent in both groups , and about half of each group had a high-risk cytogenetic profile ( 55 % in the single-AHCT arm , 50 % in the double-AHCT arm ), defined as t ( 4 ; 14 ) - , t ( 14 ; 16 ) - , or del17p-positivity .
On an intention-to-treat basis , the three-year estimate of progression-free survival ( PFS ; measured from the day of first randomization ) was : across all subgroups of enrolled patients , compared with single- AHCT , including those with :
• high-risk cytogenetic profile ( cyto-3 ; the presence of t ( 4 ; 14 ), t ( 14 ; 16 ), or del17p ): HR = 0.42 ( 95 % CI 0.21-0.84 ; p = 0.014 )
• revised ISS ( R-ISS ) stage II + III : HR = 0.64 ( 95 % CI 0.43-0.97 ; p = 0.034 )
• older age (> 55 years ): HR = 0.64 ( 95 % CI 0.43-0.96 ; p = 0.033 )
• highest-risk cytogenetic profile ( cyto-5 ; the presence of amp1q , del1p , and t ( 4 ; 14 ), t ( 14 ; 16 ), or del17p ): HR = 0.65 ( 95 % CI 0.42-1.01 ; p = 0.059 )
• very good partial response or better ( ≥VGPR ): HR = 0.64 ( 95 % CI 0.44-0.94 ; p = 0.023 )
Double-AHCT also appeared to “ overcome the adverse prognosis associated with cyto-3 risk profiles ,” Dr . Cavo noted , with similar three-year PFS rates between those with high- and standard-risk cytogenetic risk profiles ( 3-year PFS : 76 % vs . 69 %; p = 0.482 ).
In multivariate Cox regression analyses , the leading independent predictors of PFS were randomization to double-AHCT , R-ISS stage I , absence of cyto-5 risk profile , and achieving a ≥VGPR .
At the 2016 presentation , OS data were not yet mature , but with longer follow-up , Dr . Cavo and researchers were able to confirm that double-ACHT was associated with prolonged OS , compared with single-AHCT . From the time of first randomization , the three-year OS rate was 89 percent with double-AHCT versus 82 percent with single-AHCT ( HR = 0.52 ; 95 % CI 0.31- 0.86 ; p = 0.011 ).
As a potential limitation of this study , Dr . Cavo noted that a risk-adapted approach , which wasn ’ t evaluated in this trial , might identify patients who do not require additional treatment intensification after first AHCT .
The authors report relationships with Takeda , the manufacturer of bortezomib .
• 73 % ( 95 % CI 66 % -79 %) for the double-AHCT group
• 64 % ( 95 % CI 57 % -71 %) for the single-AHCT group
This represented a 30 percent reduction in the risk of progression or death , compared with the single-AHCT group ( hazard ratio [ HR ] = 0.70 ; 95 % CI 0.50-0.98 ; p = 0.040 ).
Confirmation of PFS benefit with double-ACHT was seen
REFERENCE
Cavo M , Gay FM , Patriarca F , et al . 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 / H095 study . Abstract # 401 . Presented at the 2017 American Society of Hematology Annual Meeting , December 10 , 2017 ; Atlanta , GA .
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