Carfilzomib, Pomalidomide and Dexamethasone (KPd) in Patients with Multiple Myeloma Refractory to Bortezomib and Lenalidomide. the EMN011 Trial
Authors: Sonneveld Pieter , Zweegman Sonja , Cavo Michele , Nasserinejad Kazem , Troia Rosella , Pour Ludek , Croockewit Sandra , Corradini Paolo , Patriarca Francesca , Wu Kalung , Droogendijk Jolanda , Broyl Annemiek , Minnema Monique C , Costa Bruno , Iskander Karim Saad , Boccadoro Mario 
Published: October 2019

Abstract
Introduction and background
The treatment of patients with Multiple Myeloma (MM) with relapse or progressive disease after bortezomib, lenalidomide and high-dose therapy represents an important challenge. In the EMN02 collaborative trial newly diagnosed patients with symptomatic MM were randomized to receive VCD induction followed by HDM/ASCT or VMP, followed by a second randomization for VRD consolidation or no consolidation, followed by lenalidomide maintenance until progression (Cavo et al, ASH2017, abstract #397; Sonneveld et al, EHA2018, abstract #108). The present Phase 2 trial was designed for patients with refractory disease or first progression after inclusion in EMN02 in order to evaluate a salvage treatment with next generation proteasome inhibition and IMId, i.e., Carfilzomib, Pomalidomide and Dexamethasone. The primary endpoints were response and progression-free survival (PFS). This trial is registered at www.trialregister.nl as NTR5349 and EudraCT 2013-003265-34.
Methods
Patients who were included received four 28-days re-induction cycles of KPd, i.e. Carfilzomib (20/36mg/m2, days 1,2,8,9,15,16) with Pomalidomide (4 mg days 1-21) and Dexamethasone (20mg days 1,2,8,9,15,16). In patients who had not previously received HDM/ASCT, HDM(200 mg/m2) was administered followed by autologous stem cell transplantation with stem cells harvested during after induction therapy in the EMN02 trial. Consolidation consisted of 4 additional cycles of KPd, identical to the induction cycles. Patients with stable disease or better received Pomalidomide 4mg w/o Dexamethasone in 28 days cycles until progression.
Results
At the time of this first planned interim analysis 82 patients were registered and this analysis was performed in the first 60 patients. 48% were randomized prior HDM/ASCT and 42% VMP, and 10% were not randomized. Prior best responses in the EMN02 trial were 35% CR/sCR , 75% ≥VGPR, 97% ≥PR. The median follow-up from inclusion in EMN02 was 43 months (range 21 - 62 months). In 44 patients cytogenetic risk were known, 15 (34%) of them had high-risk FISH (del17p, t(14;16) or t(4;14)). 57 fifty-seven (95%) of patients had progressed during lenalidomide maintenance, 3 patient's data are not yet available. In the present trial 38 (63%) of patients achieved normal completion of treatment according to of the protocol. Twenty patients received their first HDM plus ASCT. Median time on therapy was 14 months. Full dose re-induction treatment according to protocol could be administered in 68% (for Carfilzomib) and 64% (for Pomalidomide) of patients respectively, while for consolidation this was 62% for both Carfilzomib and Best response on protocol was 31% CR/sCR, 65% ≥VGPR, 87% ≥PR, respectively, with no difference according to response on initial treatments. Median time to response (≥PR) was 2 months. At a median follow-up of 16.3 months (range 3 - 32 months) median PFS was 18 months with better outcome in standard risk cytogenetics (HR=0.27 (0.09, 0.83) 95% CIs vs NR) and in patients with prior VMP treatment (HR=0.49 (0.21, 1.16) 95% CIs vs NR). 48 (80%) of patients are alive and in follow-up. KPd-emerging non-hematologic grade 3 and 4 adverse events included cardiovascular (5%), respiratory (5%), infections (20%) and neuropathy (3%). There were 3 fatal SAEs not related to progression (1 patient cardiac failure, 2 patients pneumonia). KPd-emerging hematological toxicity grade 3 and 4 occurred in 30% of patients.
Discussion
This Phase 2 clinical trial demonstrates that KPd is a feasible, effective and safe triple drug regimen in RRMM patients who have been previously treated and/or are refractory to bortezomib and refractory to lenalidomide. A 87% overall response rate including 31% CR/sCR is clinically relevant in this population. Since median OS has not been reached, longer follow-up is needed.
Acknowledgments
This trial was conducted as an investigator sponsored trial in EMN and supported by independent grants and drug supply from Amgen and Celgene.

Disclosures
Sonneveld: BMS: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Corradini:Roche: Honoraria, Other: Advisory Board & Lecturer; Gilead: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Novartis: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board & Lecturer; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Janssen: Honoraria, Other: Lecturer; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Celgene: Honoraria, Other: Advisory Board & Lecturer. Patriarca:Janssen: Other: Advisory role; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Jazz: Other: Travel, accommodations, expenses; MSD Italy: Other: Advisory Role; Medac: Other: Travel, accommodations, expenses. Minnema:Celgene: Consultancy, Research Funding; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Servier: Consultancy. Costa:celgene: Employment. Iskander:amgen: Employment. Boccadoro:Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding.