Carfilzomib has good penetration throughout the body, but does not cross the blood–brain barrier. It has a very short half-life of ~30 minutes, and is metabolized extrahepatically into inactive metabolites. This means carfilzomib is not dependent on liver function, and interactions with hepatically cleared comedication are uncommon. This in contrast to bortezomib, which is mostly metabolized in the liver.12

This review provides an overview of the most important phase I, II, and III studies concerning carfilzomib in different combinations, describing efficacy and toxicity. Finally, we discuss possible treatment options for patients with RRMM, with the focus on carfilzomib-based regimens. We also provide guidelines for the clinical management of carfilzomib.

CARFILZOMIB MONOTHERAPY


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Several dosing strategies were investigated in phase I trials, which are summarized in Table 1. The maximum tolerated dose (MTD) was not reached, and the maximum dose tested was 20 mg/m2 for the first two doses, which was followed by a higher dose of 27 mg/m2 (20/27 mg/m2). This dosing regimen was used in subsequent clinical trials. However, there is still uncertainty about the most optimal dosing scheme, as exemplified by the recent ARROW study comparing once-weekly administration of carfilzomib at a higher dose vs twice-weekly lower dosing, which is discussed later.13–15

(To view a larger version of Table 1, click here.)

Carfilzomib was tested in a phase II study (PX-171–003-A1) by Siegel et al in patients with RRMM. Carfilzomib was dosed at 20 mg/m2 in the first cycle to abrogate potential tumor-lysis syndrome (TLS). Thereafter, dosing was escalated to 27 mg/m2 in cycle 2 and further cycles. In this study, dexamethasone 4 mg was given as premedication on the days of carfilzomib. A total of 266 heavily pretreated MM patients participated in this study, with median prior lines of therapy 5% and 80% of patients double-refractory. A maximum of 12 cycles were given, with 15% of patients reaching this point; 59% of patients discontinued treatment early due to progressive disease, 12% due to adverse events (AEs).

The overall response rate (ORR) was 23.7%, with a clinical benefit rate (CBR) of 37.0%. Patients who were refractory to bortezomib in their last line of therapy had an ORR of 18.6%, compared to 28.3% for patients who did not receive bortezomib in their most recent line of therapy. The duration of response (DOR) was 7.8 months for patients who had a partial response (PR) or better. Median PFS was 3.7 months, with median OS of 15.6 months, for all response-evaluable patients. Outcome was not influenced by adverse cytogenetics, renal impairment, or Eastern Cooperative Oncology Group performance score. Although 77% of patients already had grade 1 or 2 PNP at baseline, only 12.4% experienced new or progression of preexisting PNP, with only 1.1% of patients experiencing grade 3 PNP. Overall, this phase II study with carfilzomib monotherapy was very tolerable and showed notable response in a heavily pretreated group of MM patients.16

Another phase II study (PX-171–004) was conducted by Vij et al in which RRMM but bortezomib-naïve MM patients were treated with carfilzomib monotherapy. The study started with 59 patients who received carfilzomib at a dose of 20 mg/m2 without dose escalation. However, due to encouraging data from the PX-171–002 study, this study was amended, and a second cohort of 70 patients received a dose of 27 mg/m2 from the second cycle onward.

Enrolled patients had received a median of two prior lines of therapy, including steroids, immunomodulatory agents, and autologous stem-cell transplants. Cohort 1 showed an ORR of 42.4%, which increased to 52.2% in cohort 2. The CBR was 59.3% and 64.2% respectively. Median DOR was 13.1 months in cohort 1, with median PFS of 8.2 month. Neither of these was reached in cohort 2, with a median follow up of 11.5 months. One patient in cohort 1 experienced grade 3 PNP, and none in cohort 2. No patients discontinued treatment because of PNP. Overall, treatment-related AEs were similar to previous studies. This study showed promising results for carfilzomib as a single agent in a pretreated but bortezomib-naïve MM-patient population, especially taking into consideration that more than a third of the patients were able to continue treatment for >12 months without significant toxicity.17

Vij et al also conducted a carfilzomib phase II study in which RRMM patients had been previously treated with bortezomib. In this study, median prior lines of treatment was seven. All 35 patients received carfilzomib twice weekly at 20 mg/m2. The ORR was substantially lower, 17.1%, with a CBR of 31.4%. AE rates were comparable to the PX-171–003 study.18 The impact of renal insufficiency in carfilzomib treatment was investigated in a phase II trial with 50 relapsed MM patients with varying renal impairment. Also here, toxicity was manageable and independent of renal status. Dose adjustments were not necessary.19

The PX-171–003-A1 study led to FDA approval of carfilzomib monotherapy for patients with RRMM with progression during or after therapy with bortezomib and an immunomodulatory derivate (IMiD). However the European Medicines Agency (EMA) required a phase III study in order to approve carfilzomib as a single agent. Therefore, the randomized phase III FOCUS study was initiated, which compared carfilzomib monotherapy (20/27 mg/m2) with low-dose corticosteroids combined with optional cyclophosphamide in patients with at least three prior lines of therapy.16

In the FOCUS study (phase III, PX-171–011) by Hájek et al in 2017, patients with RRMM were treated with carfilzomib 20/27 mg/m2) or low-dose corticosteroids, with optional cyclophosphamide in the control arm. Low dose corticosteroids consisted of dexamethasone 6 mg or prednisone 30 mg every other day or another equivalent corticosteroid dose. Additional cyclophosphamide (50 mg) was optional, but was given to 95% of patients in the control arm.

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