Carfilzomib-Lenalidomide-Dexamethasone (Krd) Induction-Autologous Transplant (Asct)-Krd Consolidation Vs Krd 12 Cycles Vs Carfilzomib-Cyclophosphamide-Dexamethasone (Kcd) Induction-Asct-Kcd Consolidation: Analysis Of The Randomized Forte Trial In Newly Diagnosed Multiple Myeloma (Ndmm)

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/m 2 -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). Aims: The primary aim was to evaluate the efficacy and safety of KRd induction-ASCT-KRd consolidation (KRd-ASCT-KRd) vs 12 cycles of KRd (KRd12) vs KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd). Methods: NDMM pts ≤65 years were randomized (1:1:1; stratification ISS and age) to: KRd-ASCT-KRd: 4 28-day cycles with KRd induction (Carfilzomib 20/36 mg/m 2 IV days 1,2,8,9,15,16; Lenalidomide 25 mg days 1-21; dexamethasone 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12: 12 KRd cycles; KCd-ASCT-KCd: 4 28-day induction cycles with KCd (Carfilzomib 20/36 mg/m 2 IV days 1,2,8,9,15,16; Cyclophosphamide 300 mg/m 2 days 1,8,15; dexamethasone 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KCd consolidation cycles. Thereafter, pts were randomized to maintenance with Lenalidomide alone or plus Carfilzomib. Centralized minimal residual disease (MRD) evaluation - 8-color second generation flow cytometry, sensitivity 10 -5 - was performed in pts achieving ≥very good partial response (VGPR). Endpoints were pre-maintenance stringent complete response (sCR) and MRD negativity in intention-to-treat (ITT) analysis. Data cut-off was May 30, 2018. Results: 474 NDMM pts were randomized (KRd-ASCT-KRd, n=158; KRd12, n=157; KCd-ASCT-KCd, n=159) and analyzed. Pts characteristics were well balanced. Median follow-up was 20 months. Depth of response improved during treatment ( Figure ). By ITT analysis, rates of pre-maintenance sCR was similar between KRd-ASCT-KRd (41%) and KRd12 (42%), and significantly higher than with KCd-ASCT-KCd (30%; P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.047; P value KRd12 vs KCd-ASCT-KCd=0.028). Similarly, rate of ≥CR was 49% with KRd-ASCT-KRd, 52% with KRd12 and 38% with KCd-ASCT-KCd (P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.041; P value KRd12 vs KCd-ASCT-KCd=0.014) and rate of ≥CR+unconfirmed CR (missing immunofixation confirmation) raised to 60% vs 63% vs 46% in the 3 groups, respectively; rate of ≥VGPR was 88% with KRd-ASCT-KRd, 86% with KRd12 and 74% with KCd-ASCT-KCd (P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.002; P value KRd12 vs KCd-ASCT-KCd=0.008). In multivariate analysis, the main factor affecting probability of achieving ≥VGPR, ≥CR or sCR was treatment with KRd-ASCT-KRd or KRd12 vs KCd, with no significant impact of ISS Stage or FISH abnormalities. In ITT analysis (MRD missing [31/395 VGPR pts, 8%] and Conclusions: Rates of MRD negativity, sCR, ≥CR, ≥VGPR were significantly higher with KRd-ASCT-KRd and KRd12 vs KCd. At present, no differences in MRD and overall best response (sCR, ≥CR, ≥VGPR) were noticed between KRd-ASCT-KRd and KRd12; longer follow-up is needed to evaluate survival. Treatment was well tolerated. Updated data will be presented at the meeting. Disclosures 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 entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity9s 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 entity9s Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity9s 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.