Randomized phase II study of weekly carfilzomib 70 mg/m² and dexamethasone with or without cyclophosphamide in relapsed and/or refractory multiple myeloma patients

Abstract

In this randomized phase 2 study (GEM-KyCyDex), the combination of weekly carfilzomib 70 mg/m2, cyclophosphamide and dexamethasone was compared to carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM) after 1-3 prior lines (PLs). 197 patients were included and randomized 1:1 to receive KCd (97 patients) or Kd (100 patients) in 28-day cycles until progressive disease or unacceptable toxicity occurred. Patient median age was 70 years, and the median number of PLs was 1 (1-3). More than 90% of patients had previously been exposed to proteasome inhibitors, ≈70% to immunomodulators, and ≈50% were refractory to their last line (mainly lenalidomide) in both groups. After a median follow-up of 37 months, median progression-free survival (PFS) was 19.1 and 16.6 months in KCd and Kd, respectively (P=0.577). Of note, in the post hoc analysis of the lenalidomiderefractory population, the addition of cyclophosphamide to Kd resulted in a significant benefit in terms of PFS: 18.4 vs. 11.3 months (Hazard ratio 1.7 [1.1-2.7]; P=0.043). The overall response rate and the percentage of patients who achieved complete response was around 70% and 20% in both groups. The addition of cyclophosphamide to Kd did not result in any safety signal, except for severe infections (7% vs. 2%). In conclusion, the combination of cyclophosphamide with Kd 70 mg/m2 weekly does not improve outcomes as compared with Kd alone in RRMM after 1-3 PLs, but a significant benefit in PFS was observed with the triplet in the lenalidomide-refractory population. The administration of weekly carfilzomib 70 mg/m2 was safe and convenient, and, overall, the toxicity was manageable in both arms.

Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology

“…Another phase II trial compared treatment with cyclophosphamide plus carfilzomib and dexamethasone to treatment with carfilzomib and dexamethasone in patients (n5197) with relapsed/refractory MM after 1 to 3 prior lines. 39 After a median follow-up of 37 months, median PFS was 19.1 with the 3-drug regimen compared with 16.6 months with the 2-drug regimen (P5.577). 39 The combination of cyclophosphamide with carfilzomib and dexamethasone did not improve outcomes significantly compared with carfilzomib and dexamethasone alone in the overall population.…”

“…39 After a median follow-up of 37 months, median PFS was 19.1 with the 3-drug regimen compared with 16.6 months with the 2-drug regimen (P5.577). 39 The combination of cyclophosphamide with carfilzomib and dexamethasone did not improve outcomes significantly compared with carfilzomib and dexamethasone alone in the overall population. However, in a subgroup analysis of the lenalidomide-refractory population, the addition of cyclophosphamide to carfilzomib and dexamethasone resulted in a PFS benefit of 18.4 versus 11.3 months (HR, 1.7; 95% CI, 1.1-2.7; P5.043).…”

“…However, in a subgroup analysis of the lenalidomide-refractory population, the addition of cyclophosphamide to carfilzomib and dexamethasone resulted in a PFS benefit of 18.4 versus 11.3 months (HR, 1.7; 95% CI, 1.1-2.7; P5.043). 39 The panel has included carfilzomib/cyclophosphamide/ dexamethasone as treatment as an other recommended regimen for relapsed/refractory MM after 1 to 3 prior therapies.…”