Weekly Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab (wKRd-D) Combination Therapy in Newly Diagnosed Multiple Myeloma: Final Results from a Clinical and Correlative Phase 2 Study
Authors: Landgren Ola , Hultcrantz Malin , Lesokhin Alexander M. , Mailankody Sham , Hassoun Hani , Tan Carlyn , Shah Urvi A , Lu Sydney X. , Diamond Benjamin , Salcedo Meghan , Werner Kelly , Rispoli Jenna , Caple Julia , Sams Allison , Verducci Dennis , Jones Katie , Concepcion Isabel , Amanda Ciardello , Chansakul Aisara , Schlossman Julia , Tavitian Elizabet , Shekarkhand Tala , Harrison Angela , Piacentini Casey , Rustad Even H , Yellapantula Venkata , Maura Francesco , Landau Heather J , Scordo Michael , Chung David J. , Shah Gunjan , Lahoud Oscar B , Thoren Katie , Murata Kazunori , Ramanathan Lakshmi , Arcila Maria E. , Ho Caleb , Roshal Mikhail , Dogan Ahmet , Derkach Andriy , Giralt Sergio A. , Korde Neha 
Published: February 2021

INTRODUCTION. Recent studies show that ~25% of newly diagnosed multiple myeloma patients treated with 8 cycles of bortezomib, lenalidomide and dexamethasone (VRd) achieve minimal residual disease (MRD) negativity. Recently, 42% stringent complete response (sCR) rates were reported with the use of VRd combined with the CD38-targeted monoclonal antibody daratumumab (VRd-D). Here, we present the final results from a phase 2 study using weekly dosing of carfilzomib 56 mg/m2 with lenalidomide and dexamethasone in combination with daratumumab (wKRd-D). The primary endpoint of our study was to demonstrate &gt;60% and to target up to 80% MRD negativity rate with wKRd-D.

METHODS. This phase II clinical trial is based on Simon's optimal two-stage design. The wKRd-D dosing schedule is as follows: 8 cycles of treatment; 28-day cycles with IV carfilzomib 20/56 mg/m2 days 1, 8, and 15; PO lenalidomide 25 mg days 1-21; PO/IV dexamethasone 40 mg weekly cycles 1-4, 20 mg after cycle 4; and IV daratumumab 16 mg/kg days 1, 8, 15, and 22 cycles 1-2, days 1 and 15 cycles 3-6, and day 1 cycles 7-8. For fit patients, stem cell collection is recommended after 4 to 6 cycles of therapy; wKRd-D therapy resumed after collection to a total of 8 cycles wKRd-D. Treatment response is being assessed with parallel bone marrow-based MRD assays (10-color single tube flowcytometry and invivoscribe IGHV sequencing); per IMWG guidelines both MRD assays allows detection of 1 myeloma cell in 100,000 cells (10^-5). Baseline bone marrow samples are evaluated with targeted DNA sequencing for FISH-Seq and somatic mutational characteristics (myTYPE).

RESULTS. The study is fully enrolled; between October 2018 and November 2019 a total of 41 evaluable patients were enrolled. Baseline characteristics include; median age 59 years (range 30-70 years); 25 (61%) females;16 (39%) males; 20 (49%) patients had high-risk FISH/SNP signature defined as one or more of the following: 1q+, t(4;14), t(14;16), t(14;20), and 17p-. At submission of this abstract, 39 out of 41 patients have completed 8 cycles of treatment and end of treatment evaluations. Of those 39, 29 patients were MRD negative and 10 patients MRD positive. Two patients are pending end of treatment evaluations for response (currently receiving cycle 8 of wKRd-D). Thus, among patients treated on the weekly cohort (wKRd-D) and who were evaluable for the MRD primary endpoint at this analysis, we found 29/39 (74%) to be MRD negative. We further show no added major clinical toxicities with wKRd-D compared to our institution standard of care KRd. At a median follow-up of 10 months, none of the MRD negative patients have progressed. Among 29 patients found to be MRD negative after 8 cycles of wKRd-D, 2 patients have been assessed for MRD at 1 year of follow-up and 2/2 (100%) show 1-year sustained MRD negativity. There are no deaths on the study.

CONCLUSIONS. Among patients evaluable for the MRD primary endpoint, in the absence of an autologous bone marrow transplant, here we show a 29/39 (74%) MRD negativity rate among newly diagnosed multiple myeloma patients treated with wKRd-D, including weekly carfilzomib 56 mg/m2 dosing. At a median follow-up of 10 months, none of the MRD negative patients have progressed. These results compare favorably with previously published results with KRd, VRd, or VRd-D. Using optimized IV fluid management (250 ml saline prior to first dose of carfilzomib only, and thereafter no IV fluids) coupled with baseline work-up with EKG/echocardiograms for all patients, we did not observe excess rates of cardiovascular or renal adverse event. The wKRd-D dosing schedule has a total of 27 infusions and offers an attractive treatment modality for newly diagnosed multiple myeloma patients. Based on these promising results, a large randomized multi-center study ("ADVANCE") evaluating wKRd-D in relation to established standard of care has been opened for enrollment.

Disclosures

Landgren: Adaptive: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Merck: Other; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Merck: Other; Pfizer: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding. Hultcrantz:Intellisphere LLC: Consultancy; Amgen: Research Funding; GSK: Research Funding; Daiichi Sankyo: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties. Mailankody:Janssen Oncology: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding; Allogene Therapeutics: Research Funding; PleXus Communications: Honoraria; Physician Education Resource: Honoraria; Takeda Oncology: Research Funding. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Shah:Celgene/BMS: Research Funding; Physicians Education Resource: Honoraria. Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Chung:Genentech: Research Funding. Shah:Amgen Inc.: Research Funding; Janssen: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Thoren:The Binding Site: Research Funding; Sebia: Research Funding. Murata:Abbott Laboratories: Research Funding. Ho:Invivoscribe, Inc.: Honoraria. Dogan:Roche: Consultancy, Research Funding; Physicians Education Resource: Consultancy; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; EUSA Pharma: Consultancy; AbbVie: Consultancy; National Cancer Institute: Research Funding. Giralt:CSL Behring: Research Funding; Jazz: Research Funding; Actinuum: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Quintiles: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Adienne: Research Funding; Kite: Research Funding. Korde:Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.

OffLabel Disclosure:

Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone in Newly-Diagnosed Multiple Myeloma. These drugs are included in the current clinical and correlative Phase II study