Kyprolis (carfilzomib) for multiple myeloma: Dosage, Side Effects & Pregnancy Safety

What is Kyprolis (carfilzomib) and how is it used?

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

What are the most important side effects and other facts about Kyprolis (carfilzomib)?

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.

Other side effects of Kyprolis (carfilzomib)

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:

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.

What is the dosage for Kyprolis (carfilzomib)?

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

Cycle 1Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10- 14Day 15Day 16Days 17- 21Day 22Day 23Days 24-28Kyprolis (mg/m²)20–70–70—–Dexamethasone (mg)40–40–40–40–Cycles 2 to 9Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10- 14Day 15Day 16Days 17- 21Day 22Day 23Days 24-28Kyprolis (mg/m²)70–70–70—–Dexamethasone (mg)40–40–40–40-Cycles 10 and laterWeek 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10- 14Day 15Day 16Days 17- 21Day 22Day 23Days 24-28Kyprolis (mg/m²)70–70–70—–Dexamethasone (mg)40–40–40—–

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

Cycle 1Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10- 14Day 15Day 16Days 17- 21Day 22Day 23Days 24-28Kyprolis (mg/m²)2020-5656-5656—-Dexamethasone (mg)2020-2020-2020-2020-Cycles 2 and laterWeek 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10- 14Day 15Day 16Days 17- 21Day 22Day 23Days 24-28Kyprolis (mg/m²)5656-5656-5656—-Dexamethasone (mg)2020-2020-2020-2020-

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

Cycle 1Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Day 22Days 23- 28Kyprolis (mg/m²)2020-2727-2727—Dexametha sone (mg)40–40–40–40-Lenalidomide25 mg daily on Days 1-21–Cycles 2 to 12Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Day 22Days 23- 28Kyprolis (mg/m²)2727-2727-2727—Dexametha sone (mg)40–40–40–40-Lenalidomide25 mg daily on Days 1-21–Cycles 13 and later^aWeek 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Day 22Days 23- 28Kyprolis (mg/m²)2727—-2727—Dexametha sone (mg)40–40–40–40-Lenalidomide25 mg daily on Days 1-21–^a Kyprolis is administered through Cycle 18; lenalidomide and dexamethasone continue thereafter.

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)

Cycle 1Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Days 22-28Kyprolis (mg/m²)^a2020-2727-2727–Cycles 2 to 12Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Days 22-28Kyprolis (mg/m²)2727-2727-2727–Cycles 13 and laterWeek 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Days 22-28Kyprolis (mg/m²)2727—-2727–^a Dexamethasone premedication is required for each Kyprolis dose in Cycle 1.

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)

Cycle 1Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Days 22-28Kyprolis (mg/m²)^a2020-5656-5656–Cycles 2 to 12Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Days 22-28Kyprolis (mg/m²)5656-5656-5656–Cycles 13 and laterWeek 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Days 22-28Kyprolis (mg/m²)5656—-5656–^a Dexamethasone premedication is required for each Kyprolis dose in Cycle 1.

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

Hematologic ToxicityRecommended Action

ANC less than 0.5 x 10⁹/L

Withhold dose
If recovered to greater than or equal to 0.5 x 10⁹/L, continue at the same dose level
For subsequent drops to less than 0.5 x 10⁹/L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolis^a

Febrile neutropenia ANC less than 0.5 x 10⁹/L and an oral temperature more than 38.5°C or two consecutive readings of more than 38.0°C for 2 hours

Withhold dose
If ANC returns to baseline grade and fever resolves, resume at the same dose level

Platelets less than 10 x 10⁹/L or evidence of bleeding with thrombocytopenia

Withhold dose
If recovered to greater than or equal to 10 x 10⁹/L and/or bleeding is controlled, continue at the same dose level
For subsequent drops to less than 10 x 10⁹/L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolisa

Renal ToxicityRecommended Action

Serum creatinine greater than or equal to 2 x baseline, or
Creatinine clearance less than 15 mL/min, or creatinine clearance decreases to less than or equal to 50% of baseline, or need for hemodialysis

Withhold dose and continue monitoring renal function (serum creatinine or creatinine clearance)
If attributable to Kyprolis, resume when renal function has recovered to within 25% of baseline; start at 1 dose level reductiona
If not attributable to Kyprolis, dosing may be resumed at the discretion of the physician
For patients on hemodialysis receiving Kyprolis, the dose is to be administered after the hemodialysis procedure

Other Non-hematologic ToxicityRecommended Action

All other severe or life-threatening^b non-hematological toxicities

Withhold until resolved or returned to baseline
Consider restarting the next scheduled treatment at 1 dose level reduction^a

ANC = absolute neutrophil count
^a See Table 7 for dose level reductions.
^b CTCAE Grade 3 and 4.

Table 7: Dose Level Reductions for Kyprolis Toxicity

RegimenDoseFirst Dose ReductionSecond Dose ReductionThird Dose ReductionKyprolis and Dexamethasone (once weekly)70 mg/m²56 mg/m²45 mg/m²36 mg/m²^aKyprolis and Dexamethasone, or Monotherapy (twice weekly)56 mg/m²45 mg/m²36 mg/m²27 mg/m²^aRegimenDoseFirst Dose ReductionSecond Dose ReductionThird Dose ReductionKyprolis, Lenalidomide, and Dexamethasone, or Monotherapy (twice weekly)27 mg/m²20 mg/m²15 mg/m²^a—Note: Infusion times remain unchanged during dose reduction(s).
^a If toxicity persists, discontinue Kyprolis treatment.

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 (carfilzomib) contraindications, pregnancy safety and drug interactions

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.