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.

Kyprolis is supplied as a solution for intravenous administration. Kyprolis should be administered intravenously over 2 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 1, Kyprolis should be administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs.

Clinical 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% 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 2 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, unacceptable toxicity, or for a maximum of 12 cycles. Subjects received 20 mg/m2 at each dose in Cycle 1, 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% (N = 266). The median duration of response was 7.8 months.

Mechanism of Action

p>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.

Literature References

Alsina M, Trudel S, Furman RR, Rosen PJ, O'Connor OA, Comenzo RL, Wong AF, Kunkel LA, Molineaux CJ, Goy A A phase 1 single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clinical cancer research : an Official Journal of the American Association for Cancer Research. 2012 Jul 3

Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, Kukreti V, Jagannath S, McDonagh KT, Alsina M, Bahlis NJ, Reu FJ, Gabrail NY, Belch A, Matous JV, Lee P, Rosen P, Sebag M, Vesole DH, Kunkel LA, Wear SM, Wong AF, Orlowski RZ, Siegel DS. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood 2012 Jun 14;119(24):5661-70