Carfilzomib-Revlimid-Dexamethasone Vs. Carfilzomib-Thalidomide-Dexamethasone Weekly (After 2 Twice Weekly Cycles) Followed By Carfilzomib Maintenance Vs. Control in Transplant Non-Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM) - Interim Efficacy Analysis of Combined Data (AGMT MM-02)
Authors: Ludwig Heinz , Sormann Siegfried , Zojer Niklas , Andel Johannes , Hartmann Bernd L. , Tinchon Christoph , Gunsilius Eberhard , Podar Klaus , Egle Alexander , Willenbacher Wolfgang , Wöll Ewald , Ruckser Reinhard , Bozic Boris , Krauth Maria-Theresa , Petzer Andreas , Schmitt Clemens A. , Machherndl-Spandl Sigrid , Agis Hermine , Paiva Bruno , Greil Richard 
Published: February 2020

Introduction: Recent data from the ARROW and CHAMPION-1 study show significant activity of once weekly carfilzomib administration. Furthermore, the recent MUK5 and CARF studies show significantly increased PFS with carfilzomib maintenance therapy. Here, we compare 9 cycles of weekly KRd with weekly KTd (after 2 cycles of biweekly therapy) followed by a second randomization to 12 cycles of carfilzomib maintenance or observation only in elderly NDMM.
Methods: 75 of 146 planned pts (median age: 75 years, range 55-84) with NDMM have been enrolled so far in this randomized phase 2 study. Treatment regimen: Carfilzomib 20mg/m2 on day 1+2, 27mg/m2 on day 8, 9, 15 and 16; cycle 2: 27mg/m2 on day 1,2,8,9,15 and 16; Carfilzomib was switched to once weekly dosing (56mg/m2, d1, 8, 15) from cycle 3 on until cycle 9. Patients received dexamethasone weekly (20mg in pts ≥75 years) and either lenalidomide 25mg d 1-21, or thalidomide 100mg/day, day 1-28 (50mg in pts ≥75 years). Patients with ≥SD after 9 cycles were randomized to carfilzomib 56mg/m2 (or last tolerated dose) on day 1 and 15 q 4 weeks, or to control for one year. FISH testing was done according recommended standards. NGF MRD testing was done in pts reaching CR or VGPR. Survival estimates were calculated according to Kaplan-Meier. Differences in response rate were assessed using Fisher's exact test, while the Log-Rank test was used for evaluating differences in survival. This trial is registered on clinicaltrials.gov (NCT02891811).
Results: Median follow up was 11.7 months. 58 of the 75 pts completed ≥2 cycles (per protocol population (PP)), 12 pts discontinued therapy within the first 2 cycles due to AE/unacceptable toxicity [4 (5.3%)], death [3 (4%)], investigator decision [2 (2.7%)], patient's decision [2 (2.7%)], or other reason [1 (1.3%)]. As the trial is still ongoing, response rates and survival data are given for both groups (KRd and KTd) combined. Overall response was noted in 56 of the 58 pts (96.6%) with response data available, CR in 21 (36.2%), VGPR in 22 (37.9%), PR in 13 (22.4%), and MR in 2 (3.4%) pts. Of the 17 pts with MRD testing available, 47.1% achieved MRD negativity. PFS was 22.3 months in both the PP and ITT pts. Overall survival at 24 months was 78% in the ITT and 79% in the PP group, respectively.
Between very elderly pts 75 years of age or older and pts below 75 years, no difference in ORR (96.8% vs. 96.3%, p=1), ≥VGPR (67.7% vs. 81.5%, p=0.3678) and PFS was found (ITT group: 22.3 months vs. not reached, p=0.926; PP group: 22.3 months vs. not reached, p=0.895). Likewise, OS did not differ in both age groups (data not shown). Outcome was also similar between pts with and without high-risk cytogenetics: ORR 100% vs.97.1%, p=1; ≥VGPR 80% vs. 71.4%, p=1; PFS not reached vs. 22.3 months, p=0.342; OS at 24 months was 85% for high-risk and 67% for standard-risk pts.
In a safety evaluation with 66 patients, the most frequent grade 3/4 hematologic adverse events were anemia (4.5%), leukopenia (1.5%), and thrombocytopenia (6.0%). The non-hematologic grade 3/4 AEs were infections (21.2%), cardiac failure, gastrointestinal disorders, and renal impairment (6.0% each), neurologic disorders, hypertension, and rash (3.0% each), and hepatic failure, SPM, VTE, and psychiatric disorders (1.5% each).
Conclusion: Once weekly carfilzomib 56mg/m² in combination with either lenalidomide or thalidomide resulted in high response rate and deep responses including MRDneg status in 47.1% of tested elderly patients with NDMM. Results were similar in very elderly pts (³75 years) and in those aged &lt;75 years. Treatment was associated with an acceptable tolerance profile. Adverse events (mostly infections, and less frequently GI-toxicities, cardiac failure, and renal impairment) resulting in treatment discontinuations occurred mostly during cycle 1 or 2, when the twice weekly regimen was administered as run in phase.

Disclosures
Ludwig: Janssen: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; PharmaMar: Consultancy; Celgene: Speakers Bureau. Zojer:Amgen: 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. Hartmann:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: sponsoring of educational seminars; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of educational seminars. Gunsilius:Amgen: Honoraria. Podar:Janssen Pharmaceuticals: Consultancy, Honoraria; Roche Pharmaceuticals: Research Funding; Takeda: Consultancy; Celgene: Consultancy, Honoraria; Amgen Inc.: Honoraria. Egle:Celgene: Honoraria, Other: Advisory board and Travel support. Willenbacher:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commission: Research Funding; Abbvie: Consultancy, Honoraria; Tirol Program: Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Fujimoto: Consultancy, Honoraria; Merck: Consultancy, 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, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Petzer:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Personal fees; Takeda: Membership on an entity's Board of Directors or advisory committees. Machherndl-Spandl:Celgene: Other: Advisory board. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Greil:Eisai: Honoraria; Boehringer Ingelheim: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Honoraria; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Mundipharma: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sandoz: Honoraria; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Honoraria.

OffLabel Disclosure:
Carfilomib 56mg/m2 in weekly dosing in combination with either Lenalidomide and low dose dexamethasone (KRd), or with thalidomide and low dose dexamethasone (KTd) was evaluated for first line treatment in TNE NDMM patients. After 9 cycles pts were randomized to K biweekly maintenance therapy for 12 months or to observation.