KYPROLIS

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.

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.

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.

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.

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]

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]

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%).

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.

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. Cycles 2 and beyond: carfilzomib 56 mg/m2 IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. Give carfilzomib in combination with isatuximab (10 mg/kg IV weekly in cycle 1 and 10 mg/kg IV every 2 weeks for subsequent cycles) and dexamethasone (20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle). Treatment cycles are repeated every 28 days until disease progression or unacceptable toxicity. Give dexamethasone IV on the days that carfilzomib or isatuximab is administered and orally on the other scheduled days; give dexamethasone at least 30 minutes to 4 hours prior to all carfilzomib doses during the first cycle and on subsequent cycles if needed. On the days when both carfilzomib and isatuximab are administered, give dexamethasone first, then isatuximab, and carfilzomib last. 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 calculated vs. 19.15 months; hazard ratio = 0.53; 95% CI, 0.32 to 0.79; p = 0.0007) in a prespecified interim analysis of a multinational, randomized, phase 3 trial (the IKEMA trial; n = 302). Patients (median age, 64 years) in this study had received a median of 2 prior therapies; 61% of patients had previously received a stem-cell transplantation.

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.

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.