Kyprolis (carfilzomib)

Kyprolis is a prescription medication used to treat patients with relapsed or refractory multiple myeloma, which is given intravenously (IV). 

Kyprlis, a proteasome inhibitor, can be used to treat multiple myeloma in the following ways:

• as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
• or in combination with other drugs that are also used to treat multiple myeloma, including:
  • dexamethasone or
  • with lenalidomide plus dexamethasone

Cardiac Toxicities 

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Some events occurred in patients with normal baseline ventricular function.

Acute Renal Failure 

Cases of acute renal failure have occurred in patients receiving Kyprolis. Some of these events have been fatal. Renal insufficiency adverse events (including renal failure) have occurred in approximately 11% of patients treated with Kyprolis. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. 

Tumor Lysis Syndrome 

Cases of tumor lysis syndrome (TLS), including fatal outcomes, have been reported in patients who received Kyprolis. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. 

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 in approximately 1% of patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.

Pulmonary Hypertension 

Pulmonary arterial hypertension was reported in approximately 1% of patients treated with Kyprolis and was Grade 3 or greater in less than 1% of patients. 

Dyspnea 

Dyspnea was reported in 28% of patients treated with Kyprolis and was Grade 3 or greater in 4% of patients. 

Hypertension 

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis.

Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis.

Infusion Reactions 

Infusion reactions immediately following or up to 24 hours after administration of Kyprolis, including life-threatening reactions, have occurred in patients receiving Kyprolis. 

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. 

Hemorrhage 

Fatal or serious cases of hemorrhage have been reported in patients treated with Kyprolis. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis.

Thrombocytopenia 

Kyprolis causes thrombocytopenia with platelet nadirs observed between Day 8 and Day 15 of each 28-day cycle, with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in approximately 32% of patients in clinical trials with Kyprolis. 

Hepatic Toxicity and Hepatic Failure Cases of hepatic failure, including fatal cases, have been reported (< 1%) during treatment with Kyprolis. Kyprolis can cause increased serum transaminases.

Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received Kyprolis. Some of these events have been fatal.

Posterior Reversible Encephalopathy Syndrome

Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving Kyprolis. PRES, formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is a neurological disorder which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis is confirmed by neuro-radiological imaging (MRI). 

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

In a clinical trial of 955 transplant-ineligible patients with newly diagnosed multiple myeloma randomized to Kyprolis (20/36 mg/m2 by 30-minute infusion twice weekly for four of each six-week cycle), melphalan and prednisone (KMP) or bortezomib, melphalan and prednisone (VMP), a higher incidence of fatal adverse reactions (7% versus 4%) and serious adverse reactions (50% versus 42%) were observed in the KMP arm compared to patients in the VMP arm, respectively.

Embryo-Fetal Toxicity 

Based on the mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman.

The most common side effects of Kyprolis occurring in at least 20% of patients in monotherapy trials include:

• anemia,
• fatigue,
• thrombocytopenia,
• nausea,
• pyrexia,
• dyspnea,
• diarrhea,
• headache,
• cough,
• edema peripheral.

The most common side effects of Kyprolis occurring in at least 20% of patients in the combination therapy trials include:

• anemia,
• neutropenia,
• diarrhea,
• dyspnea,
• fatigue,
• thrombocytopenia,
• pyrexia,
• insomnia,
• muscle spasm,
• cough,
• upper respiratory tract infection,
• hypokalemia.

To report suspected adverse reactions, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Recommended Dosing

Kyprolis In Combination With Dexamethasone

For the combination regimen with dexamethasone alone, administer Kyprolis intravenously once weekly or twice weekly as a 30-minute infusion as described in Table 1 & 2 below.

Once Weekly 20/70 mg/m² Regimen By 30-Minute Infusion

Kyprolis is administered intravenously as a 30-minute infusion once weekly for three weeks followed by a 13-day rest period as shown in Table 1. Each 28-day period is considered one treatment cycle. Administer Kyprolis at a starting dose of 20 mg/m² in Cycle 1 on Day 1. If tolerated, escalate the dose to 70 mg/m² on Day 8 of Cycle 1. Dexamethasone 40 mg is taken by mouth or intravenously on Days 1, 8, and 15 of all cycles and on Day 22 of Cycles 1 to 9. Administer dexamethasone 30 minutes to 4 hours before Kyprolis.

Table 1: Kyprolis Once Weekly (30-Minute Infusion) in Combination with Dexamethasone

Treatment may be continued until disease progression or unacceptable toxicity occurs. Refer to the dexamethasone Prescribing Information for other information on that product.

Twice Weekly 20/56 mg/m² Regimen By 30-Minute Infusion

Kyprolis is administered intravenously as a 30-minute infusion on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 2. Each 28-day period is considered one treatment cycle. Administer Kyprolis at a starting dose of 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 56 mg/m² on Day 8 of Cycle 1. Dexamethasone 20 mg is taken by mouth or intravenously on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. Administer dexamethasone 30 minutes to 4 hours before Kyprolis.

Table 2: Kyprolis Twice Weekly (30-Minute Infusion) in Combination with Dexamethasone

Treatment may be continued until disease progression or unacceptable toxicity occurs [see Dose Modifications Based on Toxicities]. Refer to the dexamethasone Prescribing Information for other information on that product.

Kyprolis In Combination With Lenalidomide And Dexamethasone

For the combination regimen with lenalidomide and dexamethasone, administer Kyprolis intravenously as a 10-minute infusion on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 3. Each 28-day period is considered one treatment cycle. The recommended starting dose of Kyprolis is 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 27 mg/m² on Day 8 of Cycle 1. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis. Discontinue Kyprolis after Cycle 18. Lenalidomide 25 mg is taken orally on Days 1–21 and dexamethasone 40 mg by mouth or intravenously on Days 1, 8, 15, and 22 of the 28-day cycles.

Table 3: Kyprolis Twice Weekly (10-Minute Infusion) in Combination with Lenalidomide and Dexamethasone

Continue treatment until disease progression or unacceptable toxicity occurs. Refer to the lenalidomide and dexamethasone Prescribing Information for other concomitant medications, such as the use of anticoagulant and antacid prophylaxis, that may be required with those agents.

Kyprolis Monotherapy

For monotherapy, administer Kyprolis intravenously twice weekly as a 10-minute or 30-minute infusion depending on the regimen as described below.

20/27 mg/m² Twice Weekly Regimen by 10-Minute Infusion

For monotherapy using the 20/27 mg/m² regimen, administer Kyprolis intravenously as a 10-minute infusion. In Cycles 1 through 12, administer Kyprolis on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 4. Each 28-day period is considered one treatment cycle. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis (see Table 4). Premedicate with dexamethasone 4 mg orally or intravenously 30 minutes to 4 hours before each Kyprolis dose in Cycle 1, then as needed to help prevent infusion reactions. The recommended starting dose of Kyprolis is 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 27 mg/m² on Day 8 of Cycle 1. Treatment may continue until disease progression or unacceptable toxicity occurs.

Table 4: Kyprolis Monotherapy 20/27 mg/m² Twice Weekly (10-Minute Infusion)

20/56 mg/m² Twice Weekly Regimen by 30-Minute Infusion

For monotherapy using the 20/56 mg/m² regimen, administer Kyprolis intravenously as a 30-minute infusion. In Cycles 1 through 12, administer Kyprolis on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 5. Each 28-day period is considered one treatment cycle. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis (see Table 5). Premedicate with dexamethasone 8 mg orally or intravenously 30 minutes to 4 hours before each Kyprolis dose in Cycle 1, then as needed to help prevent infusion reactions. The recommended starting dose of Kyprolis is 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 56 mg/m² on Day 8 of Cycle 1. Treatment may continue until disease progression or unacceptable toxicity occurs.

Table 5: Kyprolis Monotherapy 20/56 mg/m² Twice Weekly (30-Minute Infusion)

Dose Modifications Based On Toxicities

Modify dosing based on toxicity. Recommended actions and dose modifications for Kyprolis are presented in Table 6. Dose level reductions are presented in Table 7. See the lenalidomide and dexamethasone Prescribing Information respectively for dosing recommendations.

Table 6: Dose Modifications for Toxicity^a during Kyprolis Treatment

Table 7: Dose Level Reductions for Kyprolis Toxicity

Dose Modifications For Use In Hepatic Impairment

For patients with mild or moderate hepatic impairment, reduce the dose of Kyprolis by 25%. Dosing recommendation cannot be made in patients with severe hepatic impairment.

Dosing In Patients With End Stage Renal Disease

For patients with end stage renal disease who are on hemodialysis, administer Kyprolis after the hemodialysis procedure.

• Kyprolis can cause fetal harm based on findings from animal studies and the drug’s mechanism of action. There are no studies with the use of Kyprolis in pregnant women to inform drug-associated risks of adverse developmental outcomes.
• There are no data on the presence of Kyprolis in human milk, the effects on the breastfed child, or the effects of the drug on milk production. Because many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from Kyprolis is unknown, advise nursing women not to breastfeed during treatment with Kyprolis and for 2 weeks after treatment.
• Based on its mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman.
• Advise females of reproductive potential to avoid pregnancy and use effective contraception during treatment with Kyprolis and for at least 6 months following the final dose.
• Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for at least 3 months following the final dose.
• The safety and effectiveness of Kyprolis in pediatric patients have not been established.
• The incidence of serious adverse events in patients 65 and over was higher than the incidence in younger patients. No overall differences in effectiveness were observed between older and younger patients.