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    Small Molecule Antineoplastic Proteosome Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Proteasome inhibitor
    Used for the treatment of relapsed or refractory multiple myeloma as a single-agent and in combination with dexamethasone, lenalidomide plus dexamethasone, daratumumab plus dexamethasone, or daratumumab/hyaluronidase plus dexamethasone
    Thromboprophylaxis is recommended in patients who receive carfilzomib as part of combination therapy

    COMMON BRAND NAMES

    KYPROLIS

    HOW SUPPLIED

    KYPROLIS Intravenous Inj Pwd F/Sol: 10mg, 30mg, 60mg

    DOSAGE & INDICATIONS

    For the treatment of multiple myeloma.
    NOTE: The FDA has designated carfilzomib as an orphan drug for for the treatment of multiple myeloma.
    Dose carfilzomib at a maximum body surface area (BSA) of 2.2 m2 in patients with a BSA greater than 2.2 m2; dose adjustment is not necessary for patients with a weight change of 20% or less.
    For the treatment of patients with relapsed or refractory multiple myeloma who have received 1 or more lines of therapy.
    Intravenous dosage (20 mg/m2 and 27 mg/m2 twice weekly regimen)
    Adults

    Cycle 1: 20 mg/m2 IV over 10 minutes on days 1 and 2; if tolerated, increase to a target dose of 27 mg/m2 IV over 10 minutes on days 8, 9, 15, and 16. Treatment cycles are repeated every 28 days until disease progression or unacceptable toxicity. Cycles 2 to 12: 27 mg/m2 IV over 10 minutes on days 1, 2, 8, 9, 15, and 16. Cycles 13 and beyond: 27 mg/m2 IV over 10 minutes on days 1, 2, 15, and 16. Give dexamethasone 4 mg PO or IV 30 minutes to 4 hours prior to all carfilzomib doses during cycle 1 to attenuate infusion-related reactions; continue this premedication as needed for the prevention of infusion reactions during subsequent cycles. Consider antiviral prophylaxis during therapy and prehydration with both oral fluids (30 mL/kg at least 48 hours before day 1 of cycle 1) and IV fluids (250 to 500 mL prior to each carfilzomib dose in cycle 1). Additional IV hydration (250 to 500 mL) may be given after the carfilzomib infusion in cycle 1. Oral and/or IV hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs. Single-agent carfilzomib (mean treatment duration, 3 months) led to an overall response rate (ORR) of 23.7% (95% CI, 18.7% to 29.4%) in patients with relapsed multiple myeloma who failed a median of 5 prior therapies (including bortezomib and thalidomide and/or lenalidomide) in a multicenter, single-arm, phase II trial (n = 266; PX-171-003 trial). The median duration of response was 7.8 months, the median progression-free survival (PFS) time was 3.7 months, and the median overall survival time was 15.6 months. Additionally, the ORR was 29.6% in 71 patients with unfavorable cytogenetic/FISH markers. The ORR after 6 cycles was 52.2% in a cohort of patients with relapsed or refractory multiple myeloma who had received a median of 2 prior therapies that did not include a proteasome inhibitor (bortezomib-naive, n = 67) in another multicenter, single-arm, phase II trial (PX-171-004 trial). The 9-month PFS rate was 62.3% at a median follow-up time of 11.5 months.

    Intravenous dosage (20 mg/m2 and 56 mg/m2 twice weekly regimen)
    Adults

    Cycle 1: 20 mg/m2 IV over 30 minutes on days 1 and 2; if tolerated, increase to a target dose of 56 mg/m2 IV over 30 minutes on days 8, 9, 15, and 16. Treatment cycles are repeated every 28 days until disease progression or unacceptable toxicity. Cycles 2 to 12: 56 mg/m2 IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. Cycles 13 and beyond: 56 mg/m2 IV over 30 minutes on days 1, 2, 15, and 16. Give dexamethasone 8 mg PO or IV 30 minutes to 4 hours prior to all carfilzomib doses during cycle 1 to attenuate infusion-related reactions; continue this premedication as needed for the prevention of infusion reactions during subsequent cycles. Consider antiviral prophylaxis during therapy and prehydration with both oral fluids (30 mL/kg at least 48 hours before day 1 of cycle 1) and IV fluids (250 to 500 mL prior to each carfilzomib dose in cycle 1). Additional IV hydration (250 to 500 mL) may be given after the carfilzomib infusion in cycle 1. Oral and/or IV hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs. The overall response rate was 50% in a cohort of patients who received a carfilzomib 56-mg/m2 dosing regimen using a 30-minute infusion time (n = 24) in a multicenter, open-label, dose-escalation, phase I trial. The median time to response was 0.5 months, the median duration of response was 8 months, and the median progression-free survival time was 7 months.

    For the treatment of relapsed or refractory multiple myeloma in patients who have received 1 to 3 prior lines of therapy, in combination with lenalidomide and dexamethasone.
    Intravenous dosage
    Adults

    Cycle 1: carfilzomib 20 mg/m2 IV over 10 minutes on days 1 and 2; if tolerated, increase to a target dose of 27 mg/m2 IV over 10 minutes on days 8, 9, 15, and 16. Treatment cycles are repeated every 28 days until disease progression or unacceptable toxicity; maximum of 18 cycles for carfilzomib only. Give carfilzomib in combination with lenalidomide (25 mg PO once daily for 21 days of each cycle) and dexamethasone (40 mg PO/IV on days 1, 8, 15, and 22 of each cycle). Cycles 2 to 12: carfilzomib 27 mg/m2 IV over 10 minutes on days 1, 2, 8, 9, 15, and 16. Cycles 13 to 18: carfilzomib 27 mg/m2 IV over 10 minutes on days 1, 2, 15, and 16. Give dexamethasone 30 minutes to 4 hours prior to the carfilzomib (on carfilzomib dosing days only). Thromboprophylaxis is recommended; the choice of agent should be based on an assessment of the patient's underlying risks. Consider antiviral prophylaxis during therapy and prehydration with both oral fluids (30 mL/kg at least 48 hours before day 1 of cycle 1) and IV fluids (250 to 500 mL prior to each carfilzomib dose in cycle 1). Additional IV hydration (250 to 500 mL) may be given after the carfilzomib infusion in cycle 1. Oral and/or IV hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs. In a prespecified interim analysis of a multinational, randomized, open-label, phase III trial (n = 792; the ASPIRE trial), the median progression-free survival time (primary endpoint) was significantly increased with carfilzomib plus lenalidomide/dexamethasone compared with lenalidomide/dexamethasone alone (26.3 months vs. 17.6 months; hazard ratio (HR) = 0.69; 95% CI, 0.57 to 0.83; p = 0.0001) in patients with relapsed multiple myeloma who had received 1 to 3 prior therapies (age range, 31 to 91 years; median of 2 prior therapies). In this study, some patients had previously received bortezomib (65.8%) and/or lenalidomide (19.8%). Additionally, the median overall survival time was significantly improved in the carfilzomib/lenalidomide/dexamethasone arm compared with the lenalidomide/dexamethasone arm (48.3 months vs. 40.4 months; HR = 0.79; 95% CI, 0.67 to 0.95; p = 0.0045) at a median follow-up of 67.1 months.

    For the treatment of relapsed or refractory multiple myeloma in patients who have received 1 to 3 prior lines of therapy, in combination with dexamethasone.
    Intravenous dosage (20 mg/m2 and 56 mg/m2 twice weekly regimen)
    Adults

    Cycle 1: carfilzomib 20 mg/m2 IV over 30 minutes on days 1 and 2; if tolerated, increase to a target dose of 56 mg/m2 IV over 30 minutes on days 8, 9, 15, and 16. Treatment cycles are repeated every 28 days until disease progression or unacceptable toxicity. Give carfilzomib in combination with dexamethasone (20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle). Cycles 2 and beyond: carfilzomib 56 mg/m2 IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. Give dexamethasone 30 minutes to 4 hours prior to the carfilzomib dose. Thromboprophylaxis is recommended; the choice of agent should be based on an assessment of the patient's underlying risks. Consider antiviral prophylaxis during therapy and prehydration with both oral fluids (30 mL/kg at least 48 hours before day 1 of cycle 1) and IV fluids (250 to 500 mL prior to each carfilzomib dose in cycle 1). Additional IV hydration (250 to 500 mL) may be given after the carfilzomib infusion in cycle 1. Oral and/or IV hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs. In a prespecified interim analysis of a multinational, randomized, open-label, phase 3 trial (n = 929; the ENDEAVOR trial), the median progression-free survival (PFS) time (primary endpoint) was significantly increased with carfilzomib plus dexamethasone (median follow-up of 11.9 months) compared with bortezomib plus dexamethasone (18.7 months vs. 9.4 months; hazard ratio (HR) = 0.53; 95% CI, 0.44 to 0.65; p < 0.0001) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior therapies (age range, 30 to 89 years; median of 2 prior therapies) and had at least a partial response to 1 or more prior treatments. In this study, some patients had previously received bortezomib (54%) and/or carfilzomib (less than 1%). At a median follow-up of 37.5 months (in the carfilzomib arm), the median overall survival time was significantly improved with carfilzomib plus dexamethasone compared with bortezomib plus dexamethasone therapy (47.6 months vs. 40 months; HR = 0.791; 95% CI, 0.648 to 0.964) in the ENDEAVOR trial. The median duration of therapy in patients who received carfilzomib was 48 weeks.

    Intravenous dosage (20 mg/m2 and 70 mg/m2 once weekly regimen)
    Adults

    Cycle 1: carfilzomib 20 mg/m2 IV over 30 minutes on day 1; if tolerated, increase to a target dose of 70 mg/m2 IV over 30 minutes on days 8 and 15. Treatment cycles are repeated every 28 days until disease progression or unacceptable toxicity. Give carfilzomib in combination with dexamethasone (40 mg PO/IV on days 1, 8, 15, and 22 of cycles 1 to 9, then 40mg PO/IV on days 1, 8, and 15 on cycles 10 and beyond). Cycles 2 and beyond: carfilzomib 70mg/m2 IV over 30 minutes on days 1, 8, and 15. Give dexamethasone 30 minutes to 4 hours prior to the carfilzomib dose. Thromboprophylaxis is recommended; the choice of agent should be based on an assessment of the patient's underlying risks. Consider antiviral prophylaxis during therapy and prehydration with both oral fluids (30 mL/kg at least 48 hours before day 1 of cycle 1) and IV fluids (250 to 500 mL prior to each carfilzomib dose in cycle 1). Additional IV hydration (250 to 500 mL) may be given after the carfilzomib infusion in cycle 1. Oral and/or IV hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs.[51306] In a prespecified interim analysis of a multinational, randomized, open-label, phase 3 trial (n = 578; the ARROW trial), the median progression-free survival time (primary endpoint) was significantly increased with dexamethasone plus carfilzomib 70 mg/m2 once weekly dosing (median exposure time, 38 weeks) compared with dexamethasone plus carfilzomib 27 mg/m2 twice weekly dosing (11.2 months vs. 7.6 months; hazard ratio (HR) = 0.69; 95% CI, 0.54 to 0.88; p = 0.0029) in patients with relapsed or refractory multiple myeloma who had received 2 or 3 prior therapies including a proteasome inhibitor and an immunomodulatory agent. At a median follow-up time of 13.2 months (in the once weekly carfilzomib arm), the overall survival time had not been reached in either treatment arm (HR = 0.8; 95% CI, 0.56 to 1.14).[63629]

    For the treatment of newly diagnosed multiple myeloma in patients who are ineligible for autologous stem-cell transplant, in combination with melphalan and prednisone†.
    Intravenous dosage
    Adults

    Dosage not established. The progression-free survival (PFS) time was not significantly improved with carfilzomib, melphalan, and prednisone (KMP regimen) compared with bortezomib, melphalan, and prednisone (VMP regimen) in patients with newly diagnosed multiple myeloma who were not eligible for an autologous stem-cell transplant in a randomized, phase 3 trial (the CLARION trial). There is not sufficient evidence to support the use of this drug combination for this indication.[64061] KMP is not indicated for use in transplant-ineligible patients with newly diagnosed multiple myeloma based on data from the CLARION trial. In this trial (n = 955), PFS was not superior with KMP compared with VMP; additionally, serious (50% vs. 42%) and fatal (7% vs. 4%) adverse reactions occurred more often in the carfilzomib-containing arm.[51306]

    For the treatment of relapsed or refractory multiple myeloma in patients who have received 1 to 3 prior lines of therapy, in combination with daratumumab and dexamethasone.
    Intravenous dosage (20 mg/m2 and 56 mg/m2 twice weekly regimen)
    Adults

    Cycle 1: 20 mg/m2 IV over 30 minutes on days 1 and 2; if tolerated, increase to a target dose of 56 mg/m2 IV over 30 minutes on days 8, 9, 15, and 16. Cycles 2 and beyond: carfilzomib 56 mg/m2 IV over 30 minutes on days 1, 2, 8, 9, 15, and 16 repeated every 28 days in combination with IV daratumumab and PO/IV dexamethasone until disease progression or unacceptable toxicity. Thromboprophylaxis is recommended; the choice of agent should be based on an assessment of the patient's underlying risks. Consider antiviral prophylaxis during therapy and prehydration with both oral fluids (30 mL/kg at least 48 hours before day 1 of cycle 1) and IV fluids (250 to 500 mL prior to each carfilzomib dose in cycle 1). Additional IV hydration (250 to 500 mL) may be given after the carfilzomib infusion in cycle 1. Oral and/or IV hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs. Daratumumab is administered as follows: 8 mg/kg (actual body weight) IV on days 1 and 2 of week 1, 16 mg/kg IV weekly on weeks 2 to 8 (7 doses), 16 mg/kg IV every 2 weeks on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression. In patients 75 years or younger, give dexamethasone 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22 and 23 in cycles 1 and 2; then give dexamethasone 20 mg PO/IV on days 1, 2, 8, 9, 15, and 16 and 40 mg PO/IV on day 22 of subsequent cycles. In patients older than 75 years of age, administer dexamethasone 20 mg PO/IV on days 1 and 2 of cycle 1 and then 20 mg PO/IV weekly. Give dexamethasone 30 minutes to 4 hours prior to the carfilzomib dose. At a median follow-up time of about 17 months, the median progression-free survival was significantly improved in patients with relapsed or refractory multiple myeloma who received carfilzomib 20 mg/m2 and 56 mg/m2 twice weekly regimen, daratumumab, and dexamethasone (KdD) compared with carfilzomib and dexamethasone (Kd) alone (median time not reached vs. 15.8 months; hazard ratio = 0.63; 95% CI, 0.46 to 0.85; p = 0.0027) in a multicenter, randomized (2:1), open-label, phase 3 trial (n = 466; the CANDOR trial). The median overall survival time was not reached in either treatment arm at the time of this analysis. Patients (median age, 64 years; range, 57 to 71) in this trial had a partial response or better to at least 1 previous therapy line (median of 2 prior therapies; range, 1 to 2 therapies). In the KdD arm, more patients had a prior stem-cell transplant (63% vs. 49%) and fewer patients were 75 years of age or older (9% vs. 14%).

    Intravenous dosage (20 mg/m2 and 70 mg/m2 once weekly regimen)
    Adults

    Cycle 1: carfilzomib 20 mg/m2 IV over 30 minutes on day 1; if tolerated, increase to a target dose of 70 mg/m2 IV over 30 minutes on days 8 and 15. Cycles 2 and beyond: carfilzomib 70 mg/m2 IV over 30 minutes on days 1, 8, and 15 repeated every 28 days in combination with IV daratumumab and PO/IV dexamethasone until disease progression or unacceptable toxicity. Thromboprophylaxis is recommended; the choice of agent should be based on an assessment of the patient's underlying risks. Consider antiviral prophylaxis during therapy and prehydration with both oral fluids (30 mL/kg at least 48 hours before day 1 of cycle 1) and IV fluids (250 to 500 mL prior to each carfilzomib dose in cycle 1). Additional IV hydration (250 to 500 mL) may be given after the carfilzomib infusion in cycle 1. Oral and/or IV hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs. Daratumumab is administered as follows: 8 mg/kg (actual body weight) IV on days 1 and 2 of week 1, 16 mg/kg IV weekly on weeks 2 to 8 (7 doses), 16 mg/kg IV every 2 weeks on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression. In patients 75 years or younger, dexamethasone is administered as follows: 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, and 23 in cycles 1 and 2; 20 mg PO/IV on days 1, 2, 15, and 16 and 40 mg PO/IV on days 8 and 22 in cycles 3, 4, 5, and 6; and 20 mg PO/IV on days 1 and 2 and 40 mg PO/IV on days 8, 15, and 22 in cycles 7 and beyond. In patients older than 75 years of age, administer dexamethasone 20 mg PO/IV on days 1 and 2 of cycle 1 then 20 mg PO/IV weekly. Give dexamethasone 30 minutes to 4 hours prior to the carfilzomib dose. At a median follow-up time of 16.6 months (range, 0.5 to 27.4 months), the overall response rate was 84% (complete response rate, 33%) in patients with relapsed or refractory multiple myeloma who received carfilzomib 20 mg/m2 and 70 mg/m2 once weekly regimen, daratumumab, and dexamethasone in a multicenter, multi-arm, phase 1b trial (n = 85; EQUULEUS trial). At the time of this analysis, the median progression-free survival (PFS) time was not reached; the 12- and 18-month PFS rates were 74% and 66%, respectively. Patients (66 years; range, 38 to 85 years) in this trial had received a median of 2 prior therapies (range, 1 to 4 therapies) including bortezomib and an immunomodulatory drug; 73% of patients had received a prior autologous stem-cell transplant.

    For the treatment of relapsed or refractory multiple myeloma in patients who have received 1 to 3 prior lines of therapy, in combination with isatuximab and dexamethasone†.
    NOTE: Isatuximab is FDA approved in combination with carfilzomib and dexamethasone for this indication.
    Intravenous dosage (20 mg/m2 and 56 mg/m2 twice weekly regimen)
    Adults

    Cycle 1: 20 mg/m2 IV on days 1 and 2 and then 56 mg/m2 on days 8, 9, 15, and 16; cycle 2 and beyond: 56 mg/m2 IV on days 1, 2, 8, 9, 15, and 16. Give in combination with isatuximab (cycle 1: 10 mg/kg IV on days 1, 8, 15, and 22; cycle 2 and beyond: 10 mg/kg IV on days 1 and 15) and dexamethasone (20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23). Repeat treatment cycles every 28 days until disease progression. Give IV dexamethasone prior to isatuximab and/or carfilzomib on days these agents are given on the same day and then give dexamethasone orally for other scheduled doses. Thromboprophylaxis is recommended; the choice of agent should be based on an assessment of the patient's underlying risks. Consider antiviral prophylaxis during therapy and prehydration with both oral fluids (30 mL/kg at least 48 hours before day 1 of cycle 1) and IV fluids (250 to 500 mL prior to each carfilzomib dose in cycle 1). Additional IV hydration (250 to 500 mL) may be given after the carfilzomib infusion in cycle 1. Oral and/or IV hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs. At a median follow-up time of 20.7 months, the median progression-free survival was significantly improved in patients with relapsed or refractory multiple myeloma who received isatuximab, carfilzomib, and dexamethasone compared with carfilzomib and dexamethasone alone (median time not reached vs. 20.27 months; hazard ratio = 0.548; 95% CI, 0.366 to 0.822; p = 0.0032) in a prespecified interim analysis of a multinational, randomized, phase 3 trial (the IKEMA trial; n = 302). Patients (median age, 64 years; range, 33 to 90 years) in this study had received a median of 2 prior therapies (range, 1 to 4 therapies); 61% of patients had previously received a stem-cell transplantation.

    For the treatment of relapsed or refractory multiple myeloma in patients who have received 1 to 3 prior lines of therapy, in combination with daratumumab/hyaluronidase and dexamethasone.
    Intravenous dosage (20 mg/m2 and 56 mg/m2 twice weekly regimen)
    Adults

    Cycle 1: 20 mg/m2 IV over 30 minutes on days 1 and 2; if tolerated, increase to a target dose of 56 mg/m2 IV over 30 minutes on days 8, 9, 15, and 16. Cycles 2 and beyond: carfilzomib 56 mg/m2 IV over 30 minutes on days 1, 2, 8, 9, 15, and 16 repeated every 28 days in combination with daratumumab; hyaluronidase and PO/IV dexamethasone until disease progression or unacceptable toxicity. Thromboprophylaxis is recommended; the choice of agent should be based on an assessment of the patient's underlying risks. Consider antiviral prophylaxis during therapy and prehydration with both oral fluids (30 mL/kg at least 48 hours before day 1 of cycle 1) and IV fluids (250 to 500 mL prior to each carfilzomib dose in cycle 1). Additional IV hydration (250 to 500 mL) may be given after the carfilzomib infusion in cycle 1. Oral and/or IV hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs. Daratumumab; hyaluronidase is administered as follows: 1,800 mg daratumumab and 30,000 units hyaluronidase subcutaneously weekly on weeks 1 to 8 (8 doses), 1,800 mg daratumumab and 30,000 units hyaluronidase every 2 weeks on weeks 9 to 24 (8 doses), and then 1,800 mg daratumumab and 30,000 units hyaluronidase every 4 weeks starting on week 25 until disease progression. In patients 75 years or younger, give dexamethasone 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22 and 23 in cycles 1 and 2; then give dexamethasone 20 mg PO/IV on days 1, 2, 8, 9, 15, and 16 and 40 mg PO/IV on day 22 of subsequent cycles. In patients older than 75 years of age, administer dexamethasone 20 mg PO/IV on days 1 and 2 on week 1 of cycle 1 and then 20 mg PO/IV weekly. Give dexamethasone 30 minutes to 4 hours prior to the carfilzomib dose. The overall response rate was 84.8% in 66 patients with relapsed or refractory multiple myeloma who received a once-weekly carfilzomib regimen, daratumumab/hyaluronidase, and dexamethasone in a multicohort, phase 2 trial (the PLEIADES trial). The stringent complete response rate was 16.7% and the complete response rate was 21.2%. At a median follow-up time of 9.2 months, the median duration of response was not reached. Patients (median age, 61 years; range, 42 to 84 years) in this trial had received at least 1 previous therapy line that contained lenalidomide; 79% of patients had a prior stem-cell transplant.

    Intravenous dosage (20 mg/m2 and 70 mg/m2 once weekly regimen)
    Adults

    Cycle 1: carfilzomib 20 mg/m2 IV over 30 minutes on day 1; if tolerated, increase to a target dose of 70 mg/m2 IV over 30 minutes on days 8 and 15. Cycles 2 and beyond: carfilzomib 70 mg/m2 IV over 30 minutes on days 1, 8, and 15 repeated every 28 days in combination with daratumumab; hyaluronidase and PO/IV dexamethasone until disease progression or unacceptable toxicity. Thromboprophylaxis is recommended; the choice of agent should be based on an assessment of the patient's underlying risks. Consider antiviral prophylaxis during therapy and prehydration with both oral fluids (30 mL/kg at least 48 hours before day 1 of cycle 1) and IV fluids (250 to 500 mL prior to each carfilzomib dose in cycle 1). Additional IV hydration (250 to 500 mL) may be given after the carfilzomib infusion in cycle 1. Oral and/or IV hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs. Daratumumab; hyaluronidase is administered as follows: 1,800 mg daratumumab and 30,000 units hyaluronidase subcutaneously weekly on weeks 1 to 8 (8 doses), 1,800 mg daratumumab and 30,000 units hyaluronidase every 2 weeks on weeks 9 to 24 (8 doses), and then 1,800 mg daratumumab and 30,000 units hyaluronidase every 4 weeks starting on week 25 until disease progression. In patients 75 years or younger, dexamethasone is administered as follows: 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, and 23 in cycles 1 and 2; 20 mg PO/IV on days 1, 2, 15, and 16 and 40 mg PO/IV on days 8 and 22 in cycles 3, 4, 5, and 6; and 20 mg PO/IV on days 1 and 2 and 40 mg PO/IV on days 8, 15, and 22 in cycles 7 and beyond. In patients older than 75 years of age (or patients with a BMI less than 18.5), administer dexamethasone 20 mg PO/IV on days 1 and 2 on week 1 of cycle 1 then 20 mg PO/IV weekly. Give dexamethasone 30 minutes to 4 hours prior to the carfilzomib dose. The overall response rate was 84.8% in 66 patients with relapsed or refractory multiple myeloma who received carfilzomib (20 mg/m2 and 70 mg/m2 once weekly regimen), daratumumab/hyaluronidase, and dexamethasone in a multicohort, phase 2 trial (the PLEIADES trial). The stringent complete response rate was 16.7% and the complete response rate was 21.2%. At a median follow-up time of 9.2 months, the median duration of response was not reached. Patients (median age, 61 years; range, 42 to 84 years) in this trial had received at least 1 previous therapy line that contained lenalidomide; 79% of patients had a prior stem-cell transplant.

    MAXIMUM DOSAGE

    Adults

    70 mg/m2 per dose IV; doses capped at a BSA of 2.2 m2 (154 mg IV).

    Geriatric

    70 mg/m2 per dose IV; doses capped at a BSA of 2.2 m2 (154 mg IV).

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Mild and moderate hepatic impairment: Reduce the initial carfilzomib dose by 25%.
    Severe hepatic impairment: No dosage guidance is provided by the manufacturer.
    Treatment-Related Hepatotoxicity
    Grade 3 or 4 toxicity: Hold the carfilzomib dose until the toxicity is resolved or returns to baseline and consider a 1 level dose reduction when therapy is resumed.

    Renal Impairment

    A carfilzomib dose adjustment is not necessary in patients with any degree of baseline renal impairment including patients on chronic dialysis. In patients with end-stage renal disease receiving hemodialysis, administer carfilzomib after dialysis on the days dialysis is given.
    Treatment-Related Nephrotoxicity
    Serum creatinine concentration of 2-times the baseline value or greater, a creatinine clearance (CrCl) decrease of 50% or greater from baseline, a CrCl less than 15 mL/min, or a new requirement for dialysis during therapy: Hold the carfilzomib dose until renal function recovers to within 25% of baseline; resume therapy at a 1 dose level reduction if the renal dysfunction was attributed to carfilzomib.

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 1
    NIOSH (Draft) 2020 List: Table 2
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
    Emetic Risk
    Low
    Administer routine antiemetic prophylaxis prior to treatment.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Carfilzomib is administered as an intravenous (IV) infusion; do not give as an IV bolus or IV push.
    There is no data to support the use of carfilzomib with closed system transfer devices.
    Premedicate with dexamethasone 30 minutes to 4 hours as recommended to attenuate infusion-related reactions.
    Prehydrate with both oral fluids (30 mL/kg at least 48 hours before day 1 of cycle 1) and IV fluids (250 to 500 mL prior to each carfilzomib dose in cycle 1); additional IV hydration (250 to 500 mL) may be given after the carfilzomib infusion in cycle 1. Oral and/or IV hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs.
    Reconstitution:
    Using a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle), add sterile water for injection (5 mL to the 10-mg vial; 15 mL to the 30-mg vial; 29 mL to the 60-mg vial) to the inside wall of the vial to minimize foaming; the final carfilzomib concentration is 2 mg/mL.
    To mix, gently swirl and/or invert the vial slowly for about 1 minute or until the cake or powder completely dissolves. Do not shake. If foaming occurs, allow the solution to rest (about 5 minutes) or until foaming subsides.
    Discard contents remaining in the vial after removing the calculated dose; do NOT save left over portions of the vial to use for future doses.
    The dose may be drawn into a syringe or further diluted. When diluting carfilzomib, use a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to withdraw the calculated dose and then add to 50 mL or 100 mL of 5% dextrose injection bag; dilution volume depends on calculated dose and infusion time.
    Storage: the reconstituted vial, syringe, and diluted solution may be stored at room temperature (15 to 30 degrees C or 59 to 86 degrees F) for 4 hours or up to 24 hours (2 to 8 degrees C or 36 to 46 degrees F) in the refrigerator. The total time includes the time from reconstitution.
    Intravenous Infusion:
    Administer the calculated dose over 10 or 30 minutes; infusion time depends on the dose and indication.
    Do not mix or administer carfilzomib with other medicinal products.
    Flush the IV line with normal saline or 5% dextrose injection prior to and after carfilzomib administration.[51306]

    STORAGE

    KYPROLIS:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store in carton
    - Store reconstituted product in accordance with package insert instructions
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Angina, cardiac arrest, cardiac arrhythmias, cardiomyopathy, edema, heart failure, myocardial infarction, pulmonary edema

    Serious cardiac toxicity (e.g., cardiac arrest, new or worsening congestive heart failure (CHF) with decreased left ventricular function/ejection fraction and pulmonary edema, myocardial infarction (MI)/ischemia, and restrictive cardiomyopathy) has been reported with carfilzomib use; fatal cardiac arrest has occurred within a day of carfilzomib administration. Some events occurred in patients with normal baseline ventricular function. Monitor patients for signs or symptoms of cardiac failure or cardiac ischemia and fluid/volume overload (edema); adjust total IV fluids and manage symptoms promptly. Withhold therapy until recovery for grade 3 or 4 cardiac adverse events. Restart carfilzomib at a reduced dose if therapy is resumed following a benefit/risk assessment. Patients aged 75 years or older may have a higher risk of heart failure compared with younger patients. Patients with NYHA class III and IV CHF, recent MI, angina, and conduction abnormalities (i.e., cardiac arrhythmias not controlled with medication) were not included in clinical studies and may be at increased risk for cardiac complications. These patients should have a comprehensive medical assessment (e.g., blood pressure and fluid status) prior to starting and during treatment.[51306]

    Infusion-related reactions

    Infusion-related reactions may occur immediately following or up to 24 hours after carfilzomib administration. Premedication with dexamethasone is recommended to attenuate infusion-related events. Advise patients to promptly report infusion-related signs and symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina.

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) has been reported rarely with carfilzomib use; some cases were fatal. Patients with multiple myeloma and a high tumor burden may be at increased risk for TLS; consider prophylactic uric acid lowering agents in these patients. Hydrate patients well prior to administering carfilzomib. Monitor patients for evidence of TLS (e.g., hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia) during treatment. If TLS occurs, hold therapy until signs or symptoms resolve; manage symptoms promptly.

    Neutropenia, thrombocytopenia

    Hematologic toxicity including neutropenia and thrombocytopenia has been reported with carfilzomib therapy. Platelet nadirs typically occur around day 8 and 15 of each 28-day treatment cycle; counts usually return to baseline prior to the start of the next cycle. Monitor blood and platelet counts frequently during therapy. Interruption of therapy and/or a dose reduction may be necessary in patients who develop severe neutropenia or thrombocytopenia or febrile neutropenia.

    Hepatic disease, hepatotoxicity

    Hepatotoxicity (e.g., elevated hepatic enzymes and fatal hepatic failure) has been reported with carfilzomib use. Use carfilzomib with caution in patients with pre-existing hepatic disease; adverse events occurred more often in patients with hepatic impairment (63%) compared with patients with normal hepatic function (27%) in a study. Reduce the initial dose of carfilzomib in patients with mild or moderate hepatic impairment. Monitor liver function tests prior to starting carfilzomib and frequently during therapy. Interruption of therapy and a dose reduction may be necessary in patients who develop grade 3 or 4 hepatotoxicity.

    Bleeding, GI bleeding, intracranial bleeding, pulmonary bleeding

    Serious and potentially fatal bleeding (e.g., GI bleeding, pulmonary bleeding, and intracranial bleeding) has been reported with carfilzomib use. Bleeding has occurred in patients with low or normal platelet counts and in patients who were not receiving antiplatelet/anticoagulant therapy; additionally, intracranial bleeding has occurred without trauma. Promptly evaluate patients with blood loss. Interruption of therapy and/or a dose reduction may be necessary in patients who develop severe bleeding or any bleeding with thrombocytopenia.

    Hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura (TTP)

    Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura (TTP)/hemolytic-uremic syndrome (HUS)) has been reported in patients with multiple myeloma who received carfilzomib; some cases were fatal. Monitor patients for signs and symptoms of TTP (e.g., petechiae, bleeding, low platelet counts) or HUS (e.g., increased serum creatinine/BUN levels, anemia, hematuria). Discontinue therapy if TTP/HUS is suspected or diagnosed. Therapy may be restarted if TTP/HUS is excluded. The safety of restarting carfilzomib in patients who developed TTP/HUS on therapy is unknown.

    Renal failure, renal impairment

    Renal toxicity including renal failure has been reported in patients with advanced multiple myeloma who received carfilzomib; some cases were fatal. Acute renal failure occurred more often with single-agent carfilzomib therapy. Monitor renal function (e.g., serum creatinine, creatinine clearance) prior to starting carfilzomib and during therapy. Interruption of therapy or a dose reduction may be necessary in patient who develop renal toxicity. Patients with renal impairment at baseline may have a higher risk of developing fatal renal failure.

    Pneumonitis, pulmonary disease, respiratory distress syndrome

    Acute respiratory distress syndrome, acute respiratory failure, and acute diffuse infiltrative pulmonary disease (e.g., pneumonitis and interstitial lung disease) have been reported with carfilzomib use; some cases were fatal. Discontinue therapy if drug-induced pulmonary toxicity occurs. Severe dyspnea has also occurred with carfilzomib use. Exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes in patients who develop dyspnea. Hold carfilzomib until symptoms resolve or return to baseline in patients who experience grade 3 or 4 dyspnea. Resume therapy only after a benefit/risk assessment.

    Hypertension

    Severe hypertension (e.g., hypertensive crisis, hypertensive emergency) has been reported with carfilzomib use; some cases were fatal. Ensure patients have good blood pressure control prior to starting carfilzomib therapy. Monitor blood pressure regularly during therapy. Hold therapy in patients with uncontrolled hypertension. Resume therapy only after a benefit/risk assessment.

    Pulmonary hypertension

    Pulmonary arterial hypertension (PAH) has been reported with carfilzomib use. If PAH is suspected, evaluate with cardiac imaging and/or other tests as indicated. Hold carfilzomib until symptoms resolve or return to baseline in patients who develop pulmonary hypertension. Resume therapy only after a benefit/risk assessment.

    Thromboembolic disease

    Venous thromboembolic disease (e.g., deep venous thrombosis and pulmonary embolism) has been reported in patients who received carfilzomib in combination with dexamethasone or lenalidomide plus dexamethasone and in patients who received single-agent carfilzomib in clinical studies. The use of carfilzomib as part of combination therapy increases the risk of venous thromboembolic events (VTE). Therefore, thromboprophylaxis is recommended in patients who receive combination therapy; the choice of agent should be based on an assessment of the patient’s underlying risks. The use of oral contraceptives or a hormonal method of contraception may increase the risk of VTE; consider an alternative method of effective contraception in patients receiving carfilzomib as part of combination therapy.

    Encephalopathy

    Posterior reversible encephalopathy syndrome (PRES) has been reported with carfilzomib use. Symptoms of PRES include hypertension, seizures, headache, lethargy, confusion, blindness, altered consciousness, and/or other visual or neurological disturbances. Discontinue therapy if PRES is suspected or diagnosed; this syndrome may be confirmed on magnetic resonance imaging. PRES may be reversible if detected and treated early. The safety of restarting carfilzomib in patients who developed PRES on therapy is unknown.

    Immunosuppression, progressive multifocal leukoencephalopathy

    Progressive multifocal leukoencephalopathy (PML) has been reported in patients who received carfilzomib. Immunosuppression due to prior or concurrent immunosuppressive therapy may increase a patient's risk of developing PML. Evaluate patients who develop new-onset or changes in neurologic symptoms. Stop carfilzomib therapy if PML is suspected and initiate further evaluation including a neurology consult; discontinue carfilzomib if a PML diagnosis is confirmed.

    Geriatric

    In clinical studies evaluating carfilzomib therapy (n = 2,387), serious adverse events occurred more often in geriatric patients aged 65 to 74 years (58%) or 75 years or older (63%) who received carfilzomib compared with younger patients (49%). In one randomized clinical trial (n = 308), fatal adverse reactions were reported in 14% of patients aged 65 to 74 years or 75 years or older who received carfilzomib, daratumumab, and dexamethasone compared with 6% of patients aged less than 65 years.

    Pregnancy

    Carfilzomib may cause fetal harm when administered to a pregnant woman, based on the mechanism of action and animal studies. Advise females of reproductive potential to avoid becoming pregnant while taking carfilzomib. Discuss the potential hazard to the fetus if carfilzomib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicity including pre-implantation loss, early resorption and post implantation loss, and a decrease in fetal weight was observed in pregnant rabbits who received carfilzomib doses approximately 20% and 40% of the recommended human dose of 27 mg/m2.[51306]

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during carfilzomib treatment. Pregnancy testing should be performed prior to starting carfilzomib in female patients of reproductive potential. These patients should avoid pregnancy and use effective contraception (or abstain from sexual activity) during and for 6 months after the last carfilzomib dose. Due to male-mediated teratogenicity, men with female partners should avoid fathering a child and use effective contraception during and for 3 months after the last carfilzomib dose.

    Breast-feeding

    It is not known if carfilzomib is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during carfilzomib therapy and for 2 weeks after the last dose.[51306]

    ADVERSE REACTIONS

    Severe

    thrombocytopenia / Delayed / 5.0-54.0
    lymphopenia / Delayed / 0-50.0
    anemia / Delayed / 6.0-29.0
    neutropenia / Delayed / 0-27.0
    hypertension / Early / 3.0-21.0
    cardiac arrest / Early / 0-20.0
    myocardial infarction / Delayed / 0-20.0
    heart failure / Delayed / 0-20.0
    pulmonary edema / Early / 0-20.0
    renal failure (unspecified) / Delayed / 0-20.0
    hyperkalemia / Delayed / 0-20.0
    tumor lysis syndrome (TLS) / Delayed / 0-20.0
    thrombosis / Delayed / 0-20.0
    pulmonary embolism / Delayed / 0-20.0
    intracranial bleeding / Delayed / 0-20.0
    GI bleeding / Delayed / 0-20.0
    leukopenia / Delayed / 0-18.0
    fatigue / Early / 2.0-18.0
    atrial fibrillation / Early / 0-15.0
    cardiomyopathy / Delayed / 0-15.0
    hypertensive crisis / Early / 0-15.0
    stroke / Early / 0-15.0
    thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-15.0
    thrombotic microangiopathy / Delayed / 0-15.0
    leukoencephalopathy / Delayed / 0-15.0
    infection / Delayed / 0-13.0
    thromboembolism / Delayed / 2.0-13.0
    infusion-related reactions / Rapid / 0-12.0
    pericardial effusion / Delayed / 0-10.0
    hearing loss / Delayed / 0-10.0
    pancreatitis / Delayed / 0-10.0
    hypokalemia / Delayed / 0-6.0
    insomnia / Early / 0-6.0
    elevated hepatic enzymes / Delayed / 0-5.0
    hyperglycemia / Delayed / 0-5.0
    skin cancer / Delayed / 0-4.7
    dyspnea / Early / 4.0-4.0
    diarrhea / Early / 0-4.0
    back pain / Delayed / 0-4.0
    hypercalcemia / Delayed / 0-3.5
    influenza / Delayed / 0-3.5
    hypocalcemia / Delayed / 0-3.0
    asthenia / Delayed / 0-3.0
    pulmonary hypertension / Delayed / 2.0-2.0
    hepatic failure / Delayed / 2.0-2.0
    peripheral neuropathy / Delayed / 0-2.0
    fever / Early / 0-2.0
    acute respiratory distress syndrome (ARDS) / Early / 2.0-2.0
    vomiting / Early / 0-1.2
    headache / Early / 0-1.2
    peripheral edema / Delayed / 0-1.0
    chest pain (unspecified) / Early / 0-1.0
    anorexia / Delayed / 0-1.0
    nausea / Early / 0-1.0
    dizziness / Early / 0-1.0
    muscle cramps / Delayed / 0-1.0
    chills / Rapid / 0-1.0
    rash / Early / 0-1.0
    pericarditis / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    nephrotoxicity / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    progressive multifocal leukoencephalopathy / Delayed / Incidence not known
    hepatitis B exacerbation / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known

    Moderate

    dysphonia / Delayed / 0-20.0
    hypoalbuminemia / Delayed / 0-20.0
    hyperuricemia / Delayed / 0-20.0
    hypotension / Rapid / 0-20.0
    erythema / Early / 0-20.0
    cataracts / Delayed / 0-20.0
    blurred vision / Early / 0-20.0
    bleeding / Early / 0-20.0
    sinus tachycardia / Rapid / 0-15.0
    dehydration / Delayed / 0-15.0
    encephalopathy / Delayed / 0-15.0
    palpitations / Early / 0-10.0
    wheezing / Rapid / 0-10.0
    hyperbilirubinemia / Delayed / 0-10.0
    cholestasis / Delayed / 0-10.0
    delirium / Early / 0-10.0
    colitis / Delayed / 0-10.0
    pneumonitis / Delayed / 2.0-2.0
    interstitial lung disease / Delayed / 2.0-2.0
    angina / Early / Incidence not known
    edema / Delayed / Incidence not known
    confusion / Early / Incidence not known
    tracheitis / Delayed / Incidence not known

    Mild

    dyspepsia / Early / 0-20.0
    dental pain / Delayed / 0-20.0
    abdominal pain / Early / 0-20.0
    paresthesias / Delayed / 0-20.0
    hypoesthesia / Delayed / 0-20.0
    myalgia / Early / 0-20.0
    anxiety / Delayed / 0-20.0
    hyperhidrosis / Delayed / 0-20.0
    pruritus / Rapid / 0-20.0
    injection site reaction / Rapid / 0-20.0
    rhinitis / Early / 0-20.0
    pharyngitis / Delayed / 0-20.0
    tinnitus / Delayed / 0-20.0
    malaise / Early / 0-15.0
    syncope / Early / 0-10.0
    weakness / Early / 0-10.0
    urticaria / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    ocular pruritus / Rapid / Incidence not known
    lethargy / Early / Incidence not known
    sinusitis / Delayed / Incidence not known
    laryngitis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.

    PREGNANCY AND LACTATION

    Pregnancy

    Carfilzomib may cause fetal harm when administered to a pregnant woman, based on the mechanism of action and animal studies. Advise females of reproductive potential to avoid becoming pregnant while taking carfilzomib. Discuss the potential hazard to the fetus if carfilzomib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicity including pre-implantation loss, early resorption and post implantation loss, and a decrease in fetal weight was observed in pregnant rabbits who received carfilzomib doses approximately 20% and 40% of the recommended human dose of 27 mg/m2.[51306]

    It is not known if carfilzomib is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during carfilzomib therapy and for 2 weeks after the last dose.[51306]

    MECHANISM OF ACTION

    Carfilzomib is a tetrapeptide epoxyketone 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 exhibited antiproliferative and proapoptotic activity in solid and hematologic tumor cells in vitro. Additionally, carfilzomib demonstrated blood and tissue proteasome activity and delayed tumor growth in multiple myeloma models in animals. Carfilzomib differs from bortezomib in that it is an irreversible proteasome inhibitor and may be more selective for the chymotrypsin protease. Therefore, carfilzomib may lead to more sustained and selective proteasome activity and has a lower affinity to bind off-target enzymes (e.g., serine proteases). Carfilzomib has minimal cross reactivity with other protease classes and has demonstrated activity in bortezomib-resistant cell lines.

    PHARMACOKINETICS

    Carfilzomib is administered intravenously. Following a carfilzomib 20 mg/m2 IV dose, the mean steady-state volume of distribution was 28 L. In vitro, approximately 97% of carfilzomib was bound to plasma proteins (concentration range, 0.4 to 4 micromolar). Carfilzomib metabolism is rapid and extensive; peptidase cleavage and epoxide hydrolysis appear to be the primary metabolic pathways. Hepatic metabolism is minimal. Following a carfilzomib IV dose of 15 mg/m2 or greater given on day 1 of cycle 1, the elimination half-life was 1 hour or less and the systemic clearance was 151 to 263 L/hour. Half-life values were similar following a 30-minute IV infusion and a 2- to 10-minute IV infusion. About 25% of the carfilzomib dose was excreted in the urine as metabolites at 24 hours after the dose. Urinary and fecal excretion accounted for only 0.3% of the total carfilzomib dose. Proteasome chymotrypsin-like (CT-L) activity is suppressed at 1 hour after the first carfilzomib dose; additionally, proteasome inhibition lasts 48 hours or longer after the first carfilzomib dose on each week of dosing. The proteasome CT-L activity is inhibited by 80% or more when carfilzomib (15 mg/m2 or greater) is administered with or without lenalidomide and dexamethasone. Single-agent carfilzomib inhibits the proteasome subunits, low molecular mass polypeptide 2 and multicatalytic endopeptidase complex-like 1, by 26% to 32% and 41% to 49%, respectively.[51306]
     
    Affected cytochrome P450 isoenzymes or drug transporters: CYP3A, P-gp
    Because carfilzomib is extensively metabolized in the plasma, it is not likely to be affected by concomitant administration of CYP450 inhibitors and inducers or P-glycoprotein (P-gp) inhibitors or inducers. In vitro, carfilzomib demonstrated CYP3A and P-gp inhibition; it did not induce CYP1A2 or CYP3A4 isoenzymes. The pharmacokinetics of midazolam (a CYP3A substrate) were not affected by concomitant carfilzomib administration. Carfilzomib is a substrate of P-gp in vitro.[51306]

    Intravenous Route

    Following carfilzomib 20/27 mg/m2 twice weekly (2- to 10-minute infusion), 20/56 mg/m2 twice weekly (30-minute infusion), and 20/70 mg/m2 once weekly (30-minute infusion) dosing, the Cmax values at the highest dose in the first cycle of therapy were 1,282 (coefficient of variation (CV), 17%), 1,166 (CV, 29%), and 1,595 (CV, 26%) ng/mL, respectively; the average daily AUC values at steady state were 111 (CV, 34%), 228 (CV, 28%), and 150 (CV, 35%) ng X hr/mL, respectively. There is a dose-dependent increase in Cmax and AUC(inf) values in patients with multiple myeloma who received carfilzomib doses between 20 and 70 mg/m2 administered IV over 30 minutes or carfilzomib doses between 20 and 56 mg/m2 administered IV over 2 to 10 minutes. However, the Cmax values were 2- to 3-times lower following a 30-minute infusion compared with a 2- to 10-minute infusion. There was no drug accumulation following repeat administration of carfilzomib 70 mg/m2 IV over 30 minutes once weekly or carfilzomib 15 or 20 mg/m2 IV over 2 to 10 minutes twice weekly.[51306]