General Information

Kyprolis (carfilzomib) is a proteasome inhibitor. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth.

Kyprolis is specifically indicated for the treatment of multiple myeloma in patients who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. In August of 2020, the FDA expanded the use of Kyprolis to include its use in combination with Darzalex (daratumumab) plus dexamethasone (DKd) in two dosing regimens — once weekly and twice weekly — for the treatment of patients with relapsed or refractory multiple myeloma (R/R MM) who have received one to three previous lines of therapy.

Mechanism of Action

Kyprolis (carfilzomib) is a proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth.

Side Effects

Adverse events associated with the use of Kyprolis may include, but are not limited to, the following:

Fatigue

Anemia

Nausea

Thrombocytopenia

Dyspnea

Diarrhea

Pyrexia

Dosing/Administration

Kyprolis is supplied as a solution for intravenous administration. Kyprolis should be administered intravenously over two to 10 minutes on two consecutive days, each week for three weeks followed by a 12-day rest period. Each 28-day period is considered one treatment cycle. In cycle one, Kyprolis should be administered at a dose of 20 mg/m2. If tolerated in cycleone1, the dose should be escalated to 27 mg/m2 beginning in cycle two and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs.

Clinical Trial Results

FDA Approval
The FDA approval of Kyprolis was based on a single-arm, multicenter clinical trial. The trial enrolled 266 subjects with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide). Subjects were enrolled in the trial whose disease had a less than or equal to 25 percent response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. Kyprolis was administered intravenously over two to 10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression or unacceptable toxicity or for a maximum of 12 cycles. Subjects received 20 mg/m2 at each dose in cycle one, and 27 mg/m2 in subsequent cycles. To reduce the incidence and severity of fever, rigors, chills, dyspnea, myalgia and arthralgia, dexamethasone 4 mg by mouth or by intravenous infusion was administered prior to all Kyprolis doses during the first cycle and prior to all Kyprolis doses during the first dose-escalation (27 mg/m2) cycle. The primary endpoint was the overall response rate (ORR) as determined using International Myeloma Working Group criteria. The ORR (stringent complete response [sCR] + complete response [CR] + very good partial response [VGPR] + partial response [PR]) was 22.9 percent (N = 266). The median duration of response was 7.8 months.