Kd Dosing | KYPROLIS® (carfilzomib)

Kd Dosing

Meet your patients’ needs with flexible dosing options

In the ENDEAVOR trial, KYPROLIS® was administered at

Kd 56 mg/m² or 70 mg/m² dosing

In the A.R.R.O.W. trial, KYPROLIS® was administered at

Kd 56 mg/m² or 70 mg/m² dosing

Study Design and Adverse Events:

A.R.R.O.W.

Phase 3, randomized, open-label, multicenter trial (n = 478) comparing KYPROLIS^® 70 mg/m² once weekly plus dexamethasone to KYPROLIS^® 27 mg/m² twice weekly plus dexamethasone in patients with relapsed and refractory multiple myeloma who had received 2 to 3 prior lines of therapy. 478 patients were randomized 1:1 to receive KYPROLIS^® 70 mg/m² once weekly plus dexamethasone (n = 240) or KYPROLIS^® 27 mg/m² twice weekly plus dexamethasone (n = 238) for 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included ORR, OS, and safety.^2,*

Grade ≥ 3 adverse reactions of interest, Kd 70 mg/m² once weekly (n = 238) vs Kd 27 mg/m² twice weekly (n = 235): Peripheral neuropathy (0% vs <1%); acute renal failure (4% vs 6%); cardiac failure (3% vs 4%); ischemic heart disease (1% vs 1%); pulmonary hypertension (0% vs <1%).²

*Kd 27 mg/m² twice weekly is not an FDA-approved dosing regimen.

FDA, Food and Drug Administration; Kd, carfilzomib + dexamethasone; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

Kd 56 mg/m² or 70 mg/m² dosing

30 minute IV infusion

Infusion
time

30 minutes

Schedule for cycle 1, KYPROLIS® (carfilzomib) Kd priming dose 20mg² on days 1 and 2

KYPROLIS^® priming dose

20 mg/m² on Days 1 and 2 of Cycle 1 to evaluate tolerability

KYPROLIS® (carfilzomib) Kd 56mg/m² therapeutic dose

Target KYPROLIS^® therapeutic dose

56 mg/m² starting
Day 8 of Cycle 1

Treatment schedule

Administer KYPROLIS^® 56 mg/m² on 2 consecutive days each week for 3 weeks
Followed by a 12-day rest period as part of a 28-day treatment cycle
Continue until disease progression or unacceptable toxicity occurs

Kd, carfilzomib + dexamethasone..

CYCLE 1
CYCLE 2+

In Cycle 1, the 20 mg/m² priming dose is used for Days 1 and 2 to evaluate tolerability¹

Target the 56 mg/m² dose of KYPROLIS^® starting on Day 8 of Cycle 1 if the priming dose is tolerated on Days 1 and 2 of Cycle 1.¹

Kd twice weekly dosing schedule: cycle 1

*Until disease progression or unacceptable toxicity.

In Cycle 2 and beyond, the targeted label dose of KYPROLIS^® is 56 mg/m² as tolerated.^1,^*

Kd twice weekly dosing schedule: cycle 2

*Until disease progression or unacceptable toxicity.

CYCLE 1

In Cycle 1, the 20 mg/m² priming dose is used for Days 1 and 2 to evaluate tolerability¹

Target the 56 mg/m² dose of KYPROLIS^® starting on Day 8 of Cycle 1 if the priming dose is tolerated on Days 1 and 2 of Cycle 1.¹

*Until disease progression or unacceptable toxicity.
CYCLE 2+

In Cycle 2, the targeted label dose of KYPROLIS^® is 56 mg/m², as tolerated.^1,*

*Until disease progression or unacceptable toxicity.

Kd once-weekly dosing schedule

Achieve outcomes with less frequent, once-weekly 70 mg/m² Kd dosing

Kd 56 mg/m² or 70 mg/m² dosing

30 minute IV infusion

Infusion
time

30 minutes

KYPROLIS® (carfilzomib) Kd priming dose 20mg² on days 1 and 2 of cycle 1

KYPROLIS^® priming dose

20 mg/m² on Day 1
of Cycle 1 to evaluate tolerability

KYPROLIS® (carfilzomib) Kd 70mg/m² therapeutic dose

Target KYPROLIS^® therapeutic dose

70 mg/m² starting on Day 8 of Cycle 1

Treatment schedule

Administer KYPROLIS^® 70 mg/m² once weekly for 3 weeks
Followed by a 13-day rest period as part of a 28-day treatment cycle
Continue until disease progression or unacceptable toxicity occurs

CYCLE 1
CYCLES 2–9
CYCLES 10 +

In Cycle 1, the 20 mg/m² priming dose is used for Day 1 to evaluate tolerability.¹

Target the 70 mg/m² once-weekly dose of KYPROLIS^® starting on Day 8 of Cycle 1 if the priming dose is tolerated on Day 1 of Cycle 1.¹

Kd 70 mg/m² once weekly dosing schedule: cycle 1

Kd, carfilzomib + dexamethasone.

In Cycles 2–9, the targeted label dose KYPROLIS^® is 70 mg/m² once weekly as tolerated.^1,^*

Kd 70 mg/m² once weekly dosing schedule: cycle 2-9

*Until disease progression or unacceptable toxicity.

In Cycle 10 and beyond, administer KYPROLIS^® (70 mg/m²) and dexamethasone once weekly for 3 weeks followed by a 13-day rest period.^1,*

Kd 70 mg/m² once weekly dosing schedule: cycle 10 and beyond

*Until disease progression or unacceptable toxicity.

CYCLE 1

In Cycle 1, the 20 mg/m² priming dose is used for Day 1 to evaluate tolerability.¹

Target the 70 mg/m² once-weekly dose of KYPROLIS^® starting on Day 8 of Cycle 1 if the priming dose is tolerated on Day 1 of Cycle 1.¹

Kd, carfilzomib + dexamethasone.
CYCLES 2–9

In Cycles 2–9, the targeted label dose of KYPROLIS^® is 70 mg/m² once weekly as tolerated.^1,*

*Until disease progression or unacceptable toxicity.
CYCLES 10+

In Cycle 10 and beyond, administer KYPROLIS^® (70 mg/m²) and dexamethasone once weekly for 3 weeks followed by a 13-day rest period.^1,*

*Until disease progression or unacceptable toxicity.

Hands_img_Optimiing_Outcomes

Hands_img_Optimiing_Outcomes

Help your patients start and stay on KYPROLIS^®

Learn more about dosing and monitoring your patients throughout the course of their treatment.

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IMPORTANT SAFETY INFORMATION FOR KYPROLIS^®

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS^®. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of administration.
Monitor patients for signs or symptoms of cardiac failure or ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS^® for Grade 3 or 4 cardiac adverse reactions until recovery, and consider whether to restart at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate.
For patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment prior to starting treatment with KYPROLIS^® and remain under close follow-up with fluid management.

Acute Renal Failure

Cases of acute renal failure, including some fatal renal failure events, and renal insufficiency (including renal failure) have occurred. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS^® monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred. Patients with a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly, and withhold until resolved.

Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS^®.

Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS^® for PAH until resolved or returned to baseline and consider whether to restart based on a benefit/risk assessment.

Dyspnea

Dyspnea was reported in patients treated with KYPROLIS^®. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS^® for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart based on a benefit/risk assessment.

Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed, some fatal. Control hypertension prior to starting KYPROLIS^®. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS^® and evaluate. Consider whether to restart based on a benefit/risk assessment.

Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed. Provide thromboprophylaxis for patients being treated with the combination of KYPROLIS^® with dexamethasone or with lenalidomide plus dexamethasone or with daratumumab and dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
For patients using hormonal contraception associated with a risk of thrombosis, consider an alternative method of effective contraception during treatment.

Infusion-Related Reactions

Infusion-related reactions, including life-threatening reactions, have occurred. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration. Premedicate with dexamethasone to reduce the incidence and severity of infusion-related reactions.

Hemorrhage

Fatal or serious cases of hemorrhage have been reported. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.

Thrombocytopenia

KYPROLIS^® causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Monitor platelet counts frequently during treatment. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have occurred. KYPROLIS^® can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.

Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome, have occurred. Monitor for signs and symptoms of TTP/HUS. Discontinue if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS^® may be restarted. The safety of reinitiating KYPROLIS^® is not known.

Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS^®. If PRES is suspected, discontinue and evaluate with appropriate imaging. The safety of reinitiating KYPROLIS^® is not known.

Progressive Multifocal Leukoencephalopathy (PML)

Cases of PML, including fatal cases, have occurred. In addition to KYPROLIS^®, other contributary factors may include prior or concurrent use of immunosuppressive therapy. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue and initiate evaluation for PML including neurology consultation.

Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible Patients

In a clinical trial of transplant-ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS^®, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse reactions was observed in patients in the KMP arm. KMP is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.

Embryo-fetal Toxicity

KYPROLIS^® can cause fetal harm when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Females of reproductive potential should use effective contraception during treatment with KYPROLIS^® and for 6 months following the final dose. Males of reproductive potential should use effective contraception during treatment with KYPROLIS^® and for 3 months following the final dose.

Adverse Reactions

The most common adverse reactions occurring in at least 20% of patients taking KYPROLIS^® in the combination therapy trials: anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, pyrexia, cough, dyspnea, and insomnia.
The most common adverse reactions occurring in at least 20% of patients taking KYPROLIS^® in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.

Please see accompanying full Prescribing Information.

INDICATIONS

KYPROLIS^® (carfilzomib) is indicated in combination with dexamethasone, or with lenalidomide plus dexamethasone, or with daratumumab plus dexamethasone, or with daratumumab plus hyaluronidase-fihj plus dexamethasone, or with isatuximab plus dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
KYPROLIS^® is indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

IMPORTANT SAFETY INFORMATION FOR KYPROLIS^®

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS^®. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of administration.
Monitor patients for signs or symptoms of cardiac failure or ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS^® for Grade 3 or 4 cardiac adverse reactions until recovery, and consider whether to restart at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate.
For patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment prior to starting treatment with KYPROLIS^® and remain under close follow-up with fluid management.

Acute Renal Failure

Cases of acute renal failure, including some fatal renal failure events, and renal insufficiency (including renal failure) have occurred. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS^® monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred. Patients with a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly, and withhold until resolved.

Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS^®.

Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS^® for PAH until resolved or returned to baseline and consider whether to restart based on a benefit/risk assessment.

Dyspnea

Dyspnea was reported in patients treated with KYPROLIS^®. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS^® for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart based on a benefit/risk assessment.

Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed, some fatal. Control hypertension prior to starting KYPROLIS^®. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS^® and evaluate. Consider whether to restart based on a benefit/risk assessment.

Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed. Provide thromboprophylaxis for patients being treated with the combination of KYPROLIS^® with dexamethasone or with lenalidomide plus dexamethasone or with daratumumab and dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
For patients using hormonal contraception associated with a risk of thrombosis, consider an alternative method of effective contraception during treatment.

Infusion-Related Reactions

Infusion-related reactions, including life-threatening reactions, have occurred. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration. Premedicate with dexamethasone to reduce the incidence and severity of infusion-related reactions.

Hemorrhage

Fatal or serious cases of hemorrhage have been reported. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.

Thrombocytopenia

KYPROLIS^® causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Monitor platelet counts frequently during treatment. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have occurred. KYPROLIS^® can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.

Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome, have occurred. Monitor for signs and symptoms of TTP/HUS. Discontinue if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS^® may be restarted. The safety of reinitiating KYPROLIS^® is not known.

Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS^®. If PRES is suspected, discontinue and evaluate with appropriate imaging. The safety of reinitiating KYPROLIS^® is not known.

Progressive Multifocal Leukoencephalopathy (PML)

Cases of PML, including fatal cases, have occurred. In addition to KYPROLIS^®, other contributary factors may include prior or concurrent use of immunosuppressive therapy. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue and initiate evaluation for PML including neurology consultation.

Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible Patients

In a clinical trial of transplant-ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS^®, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse reactions was observed in patients in the KMP arm. KMP is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.

Embryo-fetal Toxicity

KYPROLIS^® can cause fetal harm when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Females of reproductive potential should use effective contraception during treatment with KYPROLIS^® and for 6 months following the final dose. Males of reproductive potential should use effective contraception during treatment with KYPROLIS^® and for 3 months following the final dose.

Adverse Reactions

The most common adverse reactions occurring in at least 20% of patients taking KYPROLIS^® in the combination therapy trials: anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, pyrexia, cough, dyspnea, and insomnia.
The most common adverse reactions occurring in at least 20% of patients taking KYPROLIS^® in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.

Please see accompanying full Prescribing Information.

INDICATIONS

KYPROLIS^® (carfilzomib) is indicated in combination with dexamethasone, or with lenalidomide plus dexamethasone, or with daratumumab plus dexamethasone, or with daratumumab plus hyaluronidase-fihj plus dexamethasone, or with isatuximab plus dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
KYPROLIS^® is indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

References: 1. KYPROLIS^® (carfilzomib) prescribing information, Onyx Pharmaceuticals Inc., an Amgen Inc. subsidiary. 2. Moreau P, Mateos M-V, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomized, phase 3 study. Lancet Oncol. 2018;19:953-964.