Carfilzomib, lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan

Abstract

This is the first study in which the carfilzomib, lenalidomide and dexamethasone (KRd) regimen was evaluated in heavily pretreated multiple myeloma. This study is a multicenter, open‐label phase 1 study of KRd in Japanese patients with relapsed or refractory multiple myeloma (RRMM) patients. The objectives were to evaluate the safety, tolerability, efficacy and pharmacokinetics of the regimen. Carfilzomib was administrated intravenously over 10 min on days 1, 2, 8, 9, 15 and 16 of a 28‐day cycle. In cycle 1, the dosage for days 1 and 2 was 20 mg/m2, followed by 27 mg/m2. Lenalidomide and dexamethasone were administered at 25 mg (days 1–21) and 40 mg (days 1, 8, 15 and 22), respectively. Twenty‐six patients were enrolled. Patients had received a median of four prior regimens and 88.5% and 61.5% received previous bortezomib and lenalidomide, respectively. High‐risk cytogenetics were seen in 53.8% of patients. The overall response rate was 88.5%. A higher rate of hyperglycemia was observed than in a previous carfilzomib monotherapy study, but this was attributed to dexamethasone. Carfilzomib pharmacokinetics were not affected by lenalidomide and dexamethasone. The KRd regimen was well tolerated and showed efficacy in Japanese RRMM patients.

Weekly carfilzomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma: A phase 1 and PK/PD trial

“…The PK parameters of carfilzomib, C max and AUC last increased in a dose‐dependent manner. These findings are consistent with those of 3 previous studies assessing PK parameters of carfilzomib at different doses in Japanese subjects . Furthermore, the pharmacodynamics analysis revealed that proteasome activities were well inhibited (≥90%) by the carfilzomib administration, which is also consistent with previous Japanese studies …”

“…These findings are consistent with those of 3 previous studies assessing PK parameters of carfilzomib at different doses in Japanese subjects. [5][6][7] Furthermore, the pharmacodynamics analysis revealed that proteasome activities were well inhibited (≥90%) by the carfilzomib administration, which is also consistent with previous Japanese studies. 5,6 This study had several limitations: notably, the small sample size, the lack of a comparator and the fact that it enrolled only Japanese patients.…”

“…Although cross‐trial comparisons are difficult, when we compare the findings of the present study with those of previous Japanese studies, the ORR of 83.3% with Cd in the present study was similar to that in a previous study by Suzuki et al (88.5%) in which carfilzomib was administered at a dose of 20/27 mg/m 2 in combination with lenalidomide and dexamethasone. In contrast, the ORR was comparable to the data reported in previous studies of twice weekly carfilzomib monotherapy at a dose of 20/27 mg/m 2 (22.5%) and 20/45 or 20/56 mg/m 2 (57.1%) .…”

“…The present efficacy findings indicate that the weekly Cd regimen with carfilzomib at a dose of 70 mg/m 2 has promising antitumor activity in heavily pretreated MM patients who had previously received bortezomib, lenalidomide or thalidomide. On the other hand, the incidences of infection‐related events (pneumonia, upper respiratory tract infection and nasopharyngitis), pyrexia and weight increase seem higher compared with those in previous Japanese phase 1 and 1/2 studies of carfilzomib . This indicates that patients should be carefully monitored for these AE when carfilzomib is administered at a dose of 20/70 mg/m 2 .…”

“…Both the CLd and Cd twice‐weekly regimens have been approved in the USA, Europe and Japan based on the results of these phase 3 studies. Furthermore, studies with carfilzomib monotherapy, Cd and CLd have been conducted in Japan. Although the efficacy of twice‐weekly carfilzomib, as monotherapy and in combination with other drugs (Ld and dexamethasone), has been demonstrated, the twice‐weekly dosing schedule results in some inconveniences for patients.…”