Eight versus four induction cycles of Carfilzomib, Thalidomide and Low-dose Dexamethasone: the Carthadex trial

Introduction
This phase 2 dose escalation trial investigates the combination of carfilzomib with thalidomide and dexamethasone (KTd) for induction and consolidation in transplant eligible patients with newly diagnosed multiple myeloma. Results of the first four cohorts have recently been published (Haematologica 2019). We here present the effect of intensified induction with 8 KTd as compared with 4 KTd on depth of response before and after high-dose melphalan (HDM).

Methods
Four or 8 induction cycles of KTd were used. Dose of carfilzomib was 20 mg/m2 i.v. on days 1, 2 followed by 27, 36, 45 or 56 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 and 16 of cycles 2 to 4 or 8. Thalidomide dose was 200 mg orally, days 1 through 28. Dexamethasone dose was 40 mg orally, days 1, 8, 15 and 22. After induction, stem cell harvest was performed after cyclophosphamide priming (2 to 4 g/m2) and G-CSF. Following HDM (200 mg/m2) and autologous stem cell transplantation, consolidation treatment consisted of 4 cycles KTd in the same schedule, thalidomide dose was 50mg. The primary endpoint was response after induction therapy, specifically complete response (CR) and very good partial response (VGPR). Other endpoints were safety, progression-free survival (PFS) and overall survival (OS).

Results
A total of 137 eligible patients were included. We report the response of 26 patients treated with 8 cycles KTd induction therapy versus 20 patients treated with 4 KTd, with carfilzomib at the highest dose level (56 mg/m2). Median age was 57 years. Median follow-up was 40.2 months [range 19.3-60.7 months]. Response with 8 KTd after induction was CR in 27%, ≥ VGPR in 92% and ≥ PR in 96%. With 4 KTd response after induction was CR in 20%, ≥ VGPR in 80% and ≥ PR in 90%. CR rate with 8 KTd increased to 35% after HDM and to 58% after consolidation treatment. With 4 KTd CR rate increased to 30% after HDM and 65% after consolidation treatment. Induction treatment with 8 KTd resulted in a higher level of premature stop of carfilzomib (12%) and dexamethasone (12%) than with 4 KTd (5% and 5% respectively). Cardiac events grade 3 and 4 in patients treated with 8 KTd occurred in 4 patients (15%, heart failure (2 patients) and hypertension (2 patients)). With 4 KTd heart failure grade 3 was reported in one patient (5%). However, the small sample size preclude firm conclusions about differences in toxicity and response. In patients treated with 8 KTd PFS and OS at 36 months were 66% and 92% respectively. With 4 KTd PFS and OS were 60% and 85% respectively.

Conclusions
Treatment with 8 KTd resulted in a deeper response before HDM and ASCT. However, depth of response was comparable after consolidation treatment between patients treated with 4 and 8 KTd. Cardiac toxicity and premature stop was higher in 8 KTd than with 4 KTd. Also, 8 KTd showed no improvement in PFS and OS. Therefore, we conclude that 8 KTd is not superior to 4 KTd.