Final Results of a Phase 2 Trial of Extended Treatment (tx) with Carfilzomib (CFZ), Lenalidomide (LEN), and Dexamethasone (KRd) Plus Autologous Stem Cell Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (NDMM)
Authors: Zimmerman Todd , Raje Noopur S. , Vij Ravi , Reece Donna , Berdeja Jesus G. , Stephens Leonor A , McDonnell Kathryn , Rosenbaum Cara A. , Jasielec Jagoda , Richardson Paul G , Gurbuxani Sandeep , Nam Jennifer , Severson Erica , Wolfe Brittany D. , Rosebeck Shaun , Stefka Andrew , Dytfeld Dominik , Griffith Kent , Jakubowiak Andrzej 
Published: October 2019

Abstract
Introduction
In a phase 1/2 study designed to assess KRd w/o ASCT, KRd provided a high rate of stringent complete response (sCR) (55%) in NDMM patients (pts) after a median of 24 cycles and 47.5 months (mo) of follow-up (f/u), with 4-year (yr) progression-free survival (PFS) and overall survival (OS) rates of 64% and 93%, respectively (Jakubowiak et al. Blood. 2012;120:1801-9; Jakubowiak et al, EHA 2016). To further improve response and outcomes, we designed a phase 2 study to assess KRd with ASCT.
Methods
The study enrolled ASCT-eligible pts with NDMM requiring tx per International Myeloma Working Group (IMWG) criteria with no age limitation. Pts received initial four 28-day cycles of KRd induction with CFZ IV 20/36 mg/m2 on Days (D) 1, 2, 8, 9, 15, 16 (20 mg/m2 given on D1, 2 in Cycle [C] 1 only); LEN PO D1-21 at 25 mg, DEX PO 40 mg/week followed by stem cell collection using G-CSF and plerixafor, melphalan 200 mg/m2 and ASCT, and KRd consolidations (C 5-8) using the same doses and schedule except LEN 15 mg in C5 with option to escalate to prior dose and DEX reduced to 20 mg weekly. After C8, pts received maintenance KRd for an additional 10 cycles using the same doses as in C8 except CFZ on D 1, 2, 15, 16 only. Single-agent LEN was recommended off-study after C18. The primary endpoint was rate of sCR at the end of C8, with minimal residual disease (MRD) among secondary endpoints. We estimated that an sCR rate of 50% or better for KRd plus ASCT would indicate superior outcome compared with a historical sCR rate of 30% for KRd w/o ASCT at this time point. Responses were assessed using current IMWG criteria. MRD was evaluated by 10-color multiparameter flow cytometry (MFC) with 10-4-10-5 sensitivity and by next generation sequencing (NGS) at landmark time-points: after KRd induction (after C4), ASCT, and KRd consolidation (after C8); at the end of KRd tx (after C18); and then yearly. NGS analysis was done using the immunoSEQ® MRDplatform with a threshold at 10-6 for MRD negativity. MRD-negative status required CR, as per current IMWG criteria.
Results
As of July 1, 2016, enrollment was completed (76 pts); 72 pts completed KRd induction, 71 ASCT, 66 KRd consolidation, and 44 KRd maintenance with 25 pts remaining on protocol tx. Median age was 59 y (range 40-76), ISS stage II/III 57%, high-risk cytogenetics 36% as per IMWG criteria. Efficacy and toxicity data were available for 73 pts. Based on January 1, 2016 cut-off date, response rates at the end of C8 were 96% VGPR, 73% CR, and 69% sCR. The rate of sCR has been improving during the post-transplant phase of the KRd tx, from 20% post-ASCT to 69% after 4 cycles of KRd consolidation (C8), and to 82% after 10 additional cycles of KRd maintenance (C18). MRD rates in pts evaluated to date were 82% by MFC (N=33) and 66% by NGS (N=29) at the end of C8, and 90% (N=20) and 71% (N=16), respectively, at the end of C18. MRD rates in a subset of high-risk pts evaluated for MRD were 90% by MFC (10 of 11 pts with high-risk) and 63% by NGS (6 of 8 pts) at the end of C8, and 100% (6 of 6 pts) by MFC and 80% (4 of 5) by NGS at the end of C18. After median f/u of 17.5 mo, 2-yr PFS was 97% and 2-yr OS 99% for all 76 pts. For NGS and/or MFC MRD-negative pts at the end of C8, 2-yr PFS/OS was 100% and for MRD-positive/unknown PFS was 93% and OS 98%. For high-risk disease pts (N=27), 2-yr PFS was 96%. KRd-related adverse events (AEs) were generally Grade (G) 1/2, and included (any G) for hematologic AEs thrombocytopenia (57%), lymphopenia (39%), anemia (39%), and neutropenia (28%) and for non-hematologic AEs fatigue (53%), peripheral neuropathy (39%), diarrhea (3%), and infection (34%). Most common G3/4 AEs were lymphopenia (28%), neutropenia (18%), and infections (8%). Two of 71 pts evaluated pre-transplant had asymptomatic decrease of ejection fraction (EF) 45-50%, with no baseline ECHO or MUGA, all remaining pts had normal pre-transplant EF. Updated results, including larger sample of MRD data, will be presented at the meeting, with nearly all patients completing 18 KRd cycles at the next data cut.
Conclusions
These results show that extended KRd tx with incorporated ASCT results in high rates of sCR and MRD-negative disease in both standard and high risk disease, which correspond to high rates of PFS and OS. These results compare favorably with data from the KRd w/o ASCT study, based on pre-specified improvement of sCR rate at the end of 8 cycles and beyond, and with historical studies in NDMM. These results will require validation in ongoing and planned randomized trials.

Disclosures
Vij: Janssen: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria; Celgene: Consultancy; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Reece:Merck: Research Funding; Otsuka: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Rosenbaum:Celgene: Speakers Bureau. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees. Dytfeld:Janssen Poland: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: 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.