1.1       Relapsed or Refractory Multiple Myeloma

• Kyprolis is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of 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.

2.1       Administration Precautions

• Hydration - Adequate hydration is required prior to dosing in Cycle 1, especially in patients at high-risk of tumor lysis syndrome (TLS) or renal toxicity. The recommended hydration includes both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). If needed, give an additional 250 mL to 500 mL of intravenous fluids following Kyprolis administration. Continue oral and/or intravenous hydration, as needed, in subsequent cycles. Monitor patients for evidence of volume overload and adjust hydration to individual patient needs, especially in patients with or at risk for cardiac failure [see Warnings and Precautions (5.1, 5.3)].

• Electrolyte Monitoring - Monitor serum potassium levels regularly during treatment with Kyprolis.

• Premedications - Premedicate with the recommended dose of dexamethasone for monotherapy or the recommended dexamethasone dose if on combination therapy [see Dosage and Administration (2.2)].  Administer dexamethasone orally or intravenously at least 30 minutes but no more than 4 hours prior to all doses of Kyprolis during Cycle 1 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions (5.9)]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.

• Administration - Kyprolis can be administered in a 50 mL or 100 mL intravenous bag of 5% Dextrose Injection, USP. Infuse over 10 or 30 minutes depending on the Kyprolis dose regimen [see Dosage and Administration (2.2)].  Administer as an intravenous infusion. Flush the intravenous administration line with normal saline or 5% Dextrose Injection, USP immediately before and after Kyprolis administration. Do not mix Kyprolis with or administer as an infusion with other medicinal products.

• Dose Calculation - Calculate the Kyprolis dose [see Dosage and Administration (2.2)] using the patient’s actual body surface area (BSA) at baseline. In patients with a BSA greater than 2.2 m2, calculate the dose based upon a BSA of 2.2 m2.

• Thromboprophylaxis - Thromboprophylaxis is recommended for patients being treated with the combination of Kyprolis with dexamethasone or with lenalidomide plus dexamethasone.  The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks [see Warnings and Precautions (5.8)].

• Infection Prophylaxis - Consider antiviral prophylaxis for patients being treated with Kyprolis to decrease the risk of herpes zoster reactivation.

• Patients on Hemodialysis - Administer Kyprolis after the hemodialysis procedure.

2.2       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.

Treatment may be continued until disease progression or unacceptable toxicity occurs [see Dosage and Administration (2.3)]. 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.

Treatment may be continued until disease progression or unacceptable toxicity occurs [see Dosage and Administration (2.3)]. 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.

Continue treatment until disease progression or unacceptable toxicity occurs [see Dosage and Administration (2.3)]. 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 [see Clinical Studies (14.3)]. 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 [see Dosage and Administration (2.1)]. 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.

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 [see Clinical Studies (14.3)].  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 [see Dosage and Administration (2.1)].  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.

2.3       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.

2.4       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 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.5       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.

2.6       Reconstitution and Preparation for Intravenous Administration

Kyprolis vials contain no antimicrobial preservatives and are intended for single-dose only. Unopened vials of Kyprolis are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL.

Read the complete preparation instructions prior to reconstitution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstitution/Preparation Steps:

1.       Remove vial from refrigerator just prior to use.

2.       Calculate the dose (mg/m2) and number of vials of Kyprolis required using the patient’s BSA at baseline. Patients with a BSA greater than 2.2 m2 should receive a dose based upon a BSA of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.

3.       Aseptically reconstitute each Kyprolis vial only with Sterile Water for Injection, USP using the volumes described in Table 8. Use a 21-gauge or larger needle (0.8 mm or smaller external diameter needle) to reconstitute each vial by slowly injecting Sterile Water for Injection, USP through the stopper and directing the Sterile Water for Injection, USP onto the INSIDE WALL OF THE VIAL to minimize foaming.  There is no data to support the use of closed system transfer devices with Kyprolis.

4.       Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow the solution to settle in the vial until foaming subsides (approximately 5 minutes) and the solution is clear.

5.       Visually inspect for particulate matter and discoloration prior to administration. The reconstituted product should be a clear, colorless solution and should not be administered if any discoloration or particulate matter is observed.

6.       Discard any unused portion left in the vial. DO NOT pool unused portions from the vials. DO NOT administer more than one dose from a vial.

7.       Kyprolis can be administered directly by intravenous infusion or optionally, administered in a 50 mL to 100 mL intravenous bag containing 5% Dextrose Injection, USP. Do not administer as an intravenous push or bolus.

8.       When administering in an intravenous bag, use a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to withdraw the calculated dose [see Dosage and Administration (2)] from the vial and dilute into 50 mL or 100 mL intravenous bag containing only 5% Dextrose Injection, USP (based on the calculated total dose and infusion time).

The stabilities of reconstituted Kyprolis under various temperature and container conditions are shown in Table 9.

5.1       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.  In clinical studies with Kyprolis, these events occurred throughout the course of Kyprolis therapy. Death due to cardiac arrest has occurred within one day of Kyprolis administration.  In randomized, open-label, multicenter trials for combination therapies, the incidence of cardiac failure events was 8% [see Adverse Reactions (6.1)].

Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia.  Evaluate promptly if cardiac toxicity is suspected.  Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery and consider whether to restart Kyprolis at 1 dose level reduction based on a benefit/risk assessment [see Dosage and Administration (2.3)].

While adequate hydration is required prior to each dose in Cycle 1, all patients should also be monitored for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure [see Dosage and Administration (2.1)].

In patients ≥ 75 years of age, the risk of cardiac failure is increased compared to patients ˂ 75 years of age. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure control and fluid management) prior to starting treatment with Kyprolis and remain under close follow-up [see Use in Specific Populations (8.5)].

5.2       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. The risk of fatal renal failure was greater in patients with a baseline reduced estimated creatinine clearance (calculated using Cockcroft-Gault equation). Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3)].

5.3       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. Ensure that patients are well hydrated before administration of Kyprolis in Cycle 1, and in subsequent cycles as needed [see Dosage and Administration (2.1)]. Consider uric acid-lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly, including interruption of Kyprolis until TLS is resolved [see Dosage and Administration (2.1)].

5.4       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 [see Dosage and Administration (2.3)].

5.5       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. Evaluate with cardiac imaging and/or other tests as indicated.  Withhold Kyprolis for pulmonary hypertension until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment [see Dosage and Administration (2.3)].

5.6       Dyspnea

Dyspnea was reported in 28% of patients treated with Kyprolis and was Grade 3 or greater in 4% of patients. 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 Kyprolis based on a benefit/risk assessment [see Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.4), and Adverse Reactions (6.1)].

5.7       Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis.  In a randomized, open-label, multicenter trial evaluating KRd versus Rd, the incidence of hypertension events was 17% in the KRd arm versus 9% in the Rd arm.  In a randomized, open-label, multicenter trial of Kd versus Vd, the incidence of hypertension events was 34% in the Kd arm versus 11% in the Vd arm. Some of these events have been fatal. It is recommended to control hypertension prior to starting Kyprolis.  Monitor blood pressure regularly in all patients while on Kyprolis. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment [see Dosage and Administration (2)].

5.8       Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. In a randomized, open-label, multicenter trial evaluating KRd versus Rd (with thromboprophylaxis used in both arms), the incidence of venous thromboembolic events in the first 12 cycles was 13% in the KRd arm versus 6% in the Rd arm. In a randomized, open-label, multicenter trial of Kd versus Vd, the incidence of venous thromboembolic events in months 1–6 was 9% in the Kd arm versus 2% in the Vd arm. With Kyprolis monotherapy, the incidence of venous thromboembolic events was 2%.

Thromboprophylaxis is recommended for patients being treated with the combination of Kyprolis with dexamethasone or with lenalidomide plus dexamethasone.  The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.

Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with Kyprolis in combination with dexamethasone or lenalidomide plus dexamethasone [see Use in Specific Populations (8.3)].

5.9       Infusion Reactions

Infusion reactions, 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. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Administer dexamethasone prior to Kyprolis to reduce the incidence and severity of infusion reactions [see Dosage and Administration (2)]. Inform patients of the risk and of symptoms and to contact a physician immediately if symptoms of an infusion reaction occur.

5.10       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. The bleeding can be spontaneous, and intracranial hemorrhage has occurred without trauma. Hemorrhage has been reported in patients having either low or normal platelet counts. Hemorrhage has also been reported in patients who were not on antiplatelet therapy or anticoagulation. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

5.11       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 [see Adverse Reactions (6.1)]. Thrombocytopenia was reported in approximately 32% of patients in clinical trials with Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3)]. Hemorrhage may occur [see Adverse Reactions (6.1) and Warnings and Precautions (5.10)].

5.12       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. Monitor liver enzymes regularly, regardless of baseline values. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

5.13       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. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Kyprolis and evaluate. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known [see Dosage and Administration (2.3)].

5.14       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). Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.

5.15       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. Patients in the KMP arm were observed to have a higher incidence of any grade adverse reactions involving cardiac failure (11% versus 4%), hypertension (25% versus 8%), acute renal failure (14% versus 6%), and dyspnea (18% versus 9%). This study did not meet its primary outcome measure of superiority in progression-free survival (PFS) for the KMP arm. Kyprolis in combination with melphalan and prednisone is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.

5.16       Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman. Carfilzomib administered intravenously to pregnant rabbits during organogenesis at a dose approximately 40% of the clinical dose of 27 mg/m2 based on BSA caused post-implantation loss and a decrease in fetal weight [see Use in Specific Populations (8.1)].

Females of reproductive potential should avoid becoming pregnant while being treated with Kyprolis.  Advise females of reproductive potential that they must use contraception during treatment with Kyprolis and for 6 months following the final dose.  Advise males with female sexual partners of reproductive potential that they must use contraception during treatment with Kyprolis and for 3 months following the final dose.  If Kyprolis is used during pregnancy or if the patient becomes pregnant during Kyprolis treatment, the patient should be apprised of the potential risk to the fetus [see Use in Specific Populations (8.1, 8.3) and Nonclinical Toxicology (13.1)].

6.1       Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in medical practice.

Safety Experience with Kyprolis in Combination with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma

The safety of Kyprolis in combination with lenalidomide and dexamethasone (KRd) was evaluated in an open-label randomized study in patients with relapsed multiple myeloma. Details of the study treatment are described in Section 14.1.  The median number of cycles initiated was 22 cycles for the KRd arm and 14 cycles for the Rd arm.

Deaths due to adverse reactions within 30 days of the last dose of any therapy in the KRd arm occurred in 45/392 (12%) patients compared with 42/389 (11%) patients who died due to adverse events within 30 days of the last dose of any Rd therapy. The most common cause of deaths occurring in patients (%) in the two arms (KRd versus Rd) included infection 12 (3%) versus 11 (3%), cardiac 10 (3%) versus 9 (2%), and other adverse reactions 23 (6%) versus 22 (6%). Serious adverse reactions were reported in 65% of the patients in the KRd arm and 57% of the patients in the Rd arm. The most common serious adverse reactions reported in the KRd arm as compared with the Rd arm were pneumonia (17% versus 13%), respiratory tract infection (4% versus 2%), pyrexia (4% versus 3%), and pulmonary embolism (3% versus 2%).  In patients treated with Kyprolis, 47% were 65 and over and 11% were 75 years and over. The incidence of serious adverse events was 57% in patients < 65 years of age, 73% in patients 65 to 74 years of age, and 81% in patients ≥ 75 years of age [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)]. Discontinuation due to any adverse reaction occurred in 33% in the KRd arm versus 30% in the Rd arm. Adverse reactions leading to discontinuation of Kyprolis occurred in 12% of patients and the most common reactions included pneumonia (1%), myocardial infarction (0.8%), and upper respiratory tract infection (0.8%). The incidence of cardiac failure events was 7% in the KRd arm versus 4% in the Rd arm.

Common Adverse Reactions (≥ 10%)

The adverse reactions in the first 12 cycles of therapy that occurred at a rate of 10% or greater in the KRd arm are presented in Table 10.

There were 274 (70%) patients in the KRd arm who received treatment beyond Cycle 12. There were no new clinically relevant adverse reactions that emerged in the later treatment cycles.

Adverse Reactions Occurring at a Frequency of < 10%

• Blood and lymphatic system disorders: febrile neutropenia, lymphopenia
  
• Cardiac disorders:  cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, pericardial effusion
  
• Ear and labyrinth disorders:  deafness, tinnitus
  
• Eye disorders: cataract, vision blurred
  
• Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache
  
• General disorders and administration site conditions: chills, infusion site reaction, multi-organ failure, pain
  
• Infections and infestations:  clostridium difficile colitis, influenza, lung infection, rhinitis, sepsis, urinary tract infection, viral infection
  
• Metabolism and nutrition disorders: dehydration, hyperkalemia, hyperuricemia, hypoalbuminemia, hyponatremia, tumor lysis syndrome
  
• Musculoskeletal and connective tissue disorders: muscular weakness, myalgia
  
• Nervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesia
  
• Psychiatric disorders: anxiety, delirium
  
• Renal and urinary disorders: renal failure, renal failure acute, renal impairment
  
• Respiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary embolism, pulmonary edema, pulmonary hemorrhage 
  
• Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus
  
• Vascular disorders: deep vein thrombosis, hemorrhage, hypotension

Grade 3 and higher adverse reactions that occurred during Cycles 1–12 with a substantial difference (≥ 2%) between the two arms were neutropenia, thrombocytopenia, hypokalemia, and hypophosphatemia.

Laboratory Abnormalities

Table 11 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the KRd arm for patients who received combination therapy.

Table 11: Grade 3–4 Laboratory Abnormalities (≥ 10% in the KRd Arm) in Cycles 1-12 (20/27 mg/m2 Regimen in Combination with Lenalidomide and Dexamethasone)

Safety Experience with Kyprolis in Combination with Dexamethasone in Patients with Multiple Myeloma

The safety of Kyprolis in combination with dexamethasone was evaluated in two open-label, randomized  trials (ENDEAVOR and A.R.R.O.W.) [see Clinical Studies (14.2)].

ENDEAVOR evaluated patients with relapsed or refractory multiple myeloma. The study treatment is described in Section 14.2.  Patients received treatment for a median duration of 48 weeks in the twice weekly Kyprolis/dexamethasone (Kd) 20/56 mg/m2 arm and 27 weeks in the bortezomib/dexamethasone (Vd) arm.

Deaths due to adverse reactions within 30 days of last study treatment occurred in 32/463 (7%) patients in the Kd arm and 21/456 (5%) patients in the Vd arm. The causes of death occurring in patients (%) in the two arms (Kd versus Vd) included cardiac 4 (1%) versus 5 (1%), infections 8 (2%) versus 8 (2%), disease progression 7 (2%) versus 4 (1%), pulmonary 3 (1%) versus 2 (< 1%), renal 1 (< 1%) versus 0 (0%), and other adverse events 9 (2%) versus 2 (< 1%). Serious adverse reactions were reported in 59% of the patients in the Kd arm and 40% of the patients in the Vd arm. In both treatment arms, pneumonia was the most commonly reported serious adverse reaction (8% versus 9%). In patients treated with Kyprolis, 52% were 65 and over and 17% were 75 and over. The incidence of serious adverse events was 54% in patients < 65 years of age, 60% in patients 65 to 74 years of age, and 69% in patients ≥ 75 years of age [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)]. Discontinuation due to any adverse reaction occurred in 29% in the Kd arm versus 26% in the Vd arm. The most common reaction leading to discontinuation was cardiac failure in the Kd arm (n = 8, 2%) and peripheral neuropathy in the Vd arm (n = 22, 5%). The incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm.

Common Adverse Reactions (≥ 10%)

Adverse reactions in the first 6 months of therapy that occurred at a rate of 10% or greater in the Kd arm are presented in Table 12.

The event rate of ≥ Grade 2 peripheral neuropathy in the Kd arm was 7% (95% CI:  5, 9) versus 35% (95% CI:  31, 39) in the Vd arm.

Adverse Reactions Occurring at a Frequency of < 10%

• Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy, thrombotic thrombocytopenic purpura
  
• Cardiac disorders:  atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, tachycardia
  
• Ear and labyrinth disorders:  tinnitus
  
• Eye disorders: cataract, vision blurred
  
• Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache
  
• General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain
  
• Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia
  
• Immune system disorders: drug hypersensitivity
  
• Infections and infestations: bronchopneumonia, gastroenteritis, influenza, lung infection, nasopharyngitis, pneumonia, rhinitis, sepsis, urinary tract infection, viral infection
  
• Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome
  
• Musculoskeletal and connective tissue disorders: muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia
  
• Nervous system disorders: cerebrovascular accident, dizziness, hypoesthesia, paresthesia, posterior reversible encephalopathy syndrome
  
• Psychiatric disorders: anxiety
  
• Renal and urinary disorders: renal failure, renal failure acute, renal impairment
  
• Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary embolism, pulmonary edema, pulmonary hypertension, wheezing
  
• Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash
  
• Vascular disorders: deep vein thrombosis, flushing, hypotension

Laboratory Abnormalities

Table 13 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the Kd arm.

A.R.R.O.W. evaluated patients with relapsed and refractory multiple myeloma. The study treatment is described in Section 14.2. Patients received treatment for a median duration of 38 weeks in the once weekly Kd 20/70 mg/m2 arm and 29.1 weeks in the twice weekly Kd 20/27 mg/m2 arm of A.R.R.O.W.. The safety profile for the once weekly Kd 20/70 mg/m2 regimen was similar to the twice weekly Kd 20/27 mg/m2 regimen.

Deaths due to adverse reactions within 30 days of last study treatment occurred in 22/238 (9%) patients in the Kd 20/70 mg/m2 arm and 18/235 (8%) patients in the Kd 20/27 mg/m2 arm. The most frequent fatal adverse reactions occurring in patients (%) in the two arms (once weekly Kd 20/70 mg/m2 versus twice weekly Kd 20/27 mg/m2) were sepsis 2 (< 1%) versus 2 (< 1%), septic shock 2 (< 1%) versus 1 (< 1%), and infection 2 (< 1%) versus 0 (0%).  Serious adverse reactions were reported in 43% of the patients in the Kd 20/70 mg/m2 arm and 41% of the patients in the Kd 20/27 mg/m2 arm. In both treatment arms, pneumonia was the most commonly reported serious adverse reaction (8% versus 7%). In patients treated with once weekly Kd 20/70 mg/m2, 57% were 65 and over and 19% were 75 and over. The incidence of serious adverse events was 37% in patients < 65 years of age, 50% in patients 65 to 74 years of age, and 44% in patients ≥ 75 years of age [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)]. Discontinuation due to any adverse reaction occurred in 13% in the Kd 20/70 mg/m2 arm versus 12% in the Kd 20/27 mg/m2 arm. The most common reaction leading to discontinuation was acute kidney injury (2% versus 2%). The incidence of cardiac failure events was 3.8% in the once weekly Kd 20/70 mg/m2 arm versus 5.1% in the twice weekly Kd 20/27 mg/m2 arm.

Common Adverse Reactions (≥ 10%)

Adverse reactions that occurred at a rate of 10% or greater in either Kd arm is presented in Table 14.

Adverse Reactions Occurring at a Frequency of < 10%

• Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy
  
• Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, pericardial effusion, tachycardia
  
• Ear and labyrinth disorders:  tinnitus
  
• Eye disorders: cataract, vision blurred
  
• Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, toothache, vomiting
  
• General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain
  
• Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia
  
• Infections and infestations:  clostridium difficile colitis, gastroenteritis, influenza, lung infection, nasopharyngitis, rhinitis, sepsis, septic shock, urinary tract infection, viral infection
  
• Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome
  
• Musculoskeletal and connective tissue disorders:  muscle spasms, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia
  
• Nervous system disorders: cerebrovascular accident, dizziness, paresthesia, peripheral neuropathy
  
• Psychiatric disorders: anxiety, delirium
  
• Renal and urinary disorders:  acute kidney injury, renal failure, renal impairment
  
• Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary hemorrhage, pulmonary embolism, pulmonary hypertension, pulmonary edema, wheezing
  
• Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash
  
• Vascular disorders: deep vein thrombosis, flushing, hypotension

Safety Experience with Kyprolis in Patients with Multiple Myeloma who Received Monotherapy

The safety of Kyprolis, dosed at 20/27 mg/m2 by up to 10-minute infusion, was evaluated in clinical trials in which 598 patients with relapsed and/or refractory myeloma received Kyprolis monotherapy starting with the 20 mg/m2 dose in Cycle 1, Day 1 and escalating to 27 mg/m2 on Cycle 1, Day 8 or Cycle 2, Day 1. Premedication with dexamethasone 4 mg was required before each dose in Cycle 1 and was optional for subsequent cycles. The median age was 64 years (range 32–87), and approximately 57% were male. The patients received a median of 5 (range 1–20) prior regimens. The median number of cycles initiated was 4 (range 1–35).

Serious adverse reactions, regardless of causality, were reported in 50% of patients in the pooled Kyprolis monotherapy studies (N = 598).  The most common serious adverse reactions were: pneumonia (8%), acute renal failure (5%), disease progression (4%), pyrexia (3%), hypercalcemia (3%), congestive heart failure (3%), multiple myeloma (3%), anemia (2%), and dyspnea (2%). In patients treated with Kyprolis, 49% were 65 and over, while 16% were 75 and over. The incidence of serious adverse events was 44% in patients < 65 years of age, 55% in patients 65 to 74 years of age, and 56% in patients ≥ 75 years of age [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].

Deaths due to adverse reactions within 30 days of the last dose of Kyprolis occurred in 30/598 (5%) patients receiving Kyprolis monotherapy. These adverse reactions were related to cardiac disorders in 10 (2%) patients, infections in 8 (1%) patients, renal disorders in 4 (< 1%) patients, and other adverse reactions in 8 (1%) patients.  In a randomized trial comparing Kyprolis as a single agent versus corticosteroids with optional oral cyclophosphamide for patients with relapsed and refractory multiple myeloma, mortality was higher in the patients treated with Kyprolis in comparison to the control arm in the subgroup of 48 patients ≥ 75 years of age. The most common cause of discontinuation due to an adverse reaction was acute renal failure (2%).

Safety of Kyprolis monotherapy dosed at 20/56 mg/m2 by 30-minute infusion was evaluated in a multicenter, open-label study in patients with relapsed and/or refractory multiple myeloma.  The study treatment is described in Section 14.3. The patients received a median of 4 (range 1–10) prior regimens.

The common adverse reactions occurring at a rate of 20% or greater with Kyprolis monotherapy are presented in Table 15.

Adverse Reactions Occurring at a Frequency of < 20%

• Blood and lymphatic system disorders: febrile neutropenia, leukopenia, neutropenia
  
• Cardiac disorders:  cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia
  
• Ear and labyrinth disorders:  tinnitus
  
• Eye disorders: cataract, blurred vision
  
• Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, gastrointestinal hemorrhage, toothache
  
• General disorders and administration site conditions:  asthenia, infusion site reaction, multi-organ failure, pain
  
• Hepatobiliary disorders: hepatic failure
  
• Infections and infestations: bronchitis, bronchopneumonia, influenza, lung infection, pneumonia, nasopharyngitis, respiratory tract infection, rhinitis, sepsis, urinary tract infection
  
• Metabolism and nutrition disorders:  hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome
  
• Musculoskeletal and connective tissue disorders:  arthralgia, musculoskeletal pain, musculoskeletal chest pain, myalgia, pain in extremity
  
• Nervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesia, peripheral motor neuropathy, peripheral neuropathy, peripheral sensory neuropathy
  
• Psychiatric disorders: anxiety
  
• Renal and urinary disorders:  acute renal failure, renal failure, renal impairment
  
• Respiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary edema, pulmonary hemorrhage
  
• Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash
  
• Vascular disorders: embolic and thrombotic events, venous (including deep vein thrombosis and pulmonary embolism), hemorrhage, hypotension

Grade 3 and higher adverse reactions occurring at an incidence of > 1% include febrile neutropenia, cardiac arrest, cardiac failure congestive, pain, sepsis, urinary tract infection, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hyponatremia, hypophosphatemia, renal failure, renal failure acute, renal impairment, pulmonary edema, and hypotension.

Laboratory Abnormalities

Table 16 describes Grade 3–4 laboratory abnormalities reported at a rate of > 10% for patients who received Kyprolis monotherapy.

6.2       Postmarketing Experience

The following additional adverse reactions were reported in the postmarketing experience with Kyprolis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: hemolytic uremic syndrome (HUS), gastrointestinal perforation, pericarditis, and cytomegalovirus infection including chorioretinitis, pneumonitis, enterocolitis, and viremia.

8.1       Pregnancy

Risk Summary

Kyprolis can cause fetal harm based on findings from animal studies (see Data) and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. There are no studies with the use of Kyprolis in pregnant women to inform drug-associated risks of adverse developmental outcomes.  Kyprolis caused embryo-fetal lethality in rabbits at doses lower than the clinical dose.  Advise pregnant women of the potential risk to the fetus.  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.  All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

Data

Animal Data

Carfilzomib administered intravenously to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day in rats and 0.8 mg/kg/day in rabbits. In rabbits, there was an increase in pre-implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on BSA.

8.2       Lactation

Risk Summary

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.

8.3       Females and Males of Reproductive Potential

Based on its mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Conduct pregnancy testing on females of reproductive potential prior to initiating Kyprolis treatment.

Contraception

Females

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.  

Males

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.

Infertility

Based on the mechanism of action, Kyprolis may have an effect on either male or female fertility [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)].  There are no data on the effect of Kyprolis on human fertility.

8.4       Pediatric Use

The safety and effectiveness of Kyprolis in pediatric patients have not been established.

8.5       Geriatric Use

Of 1691 patients in clinical studies of Kyprolis, 50.4% were 65 and over, while 15.4% were 75 and over. 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.

8.6       Hepatic Impairment

Reduce the dose of Kyprolis by 25% in patients with mild (total bilirubin 1 to 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment.  Dosing recommendation cannot be made for patients with severe hepatic function [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

The incidence of serious adverse events was higher in patients with mild, moderate, and severe hepatic impairment combined (22/35 or 63%) than in patients with normal hepatic function (3/11 or 27%) [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)].

12.1       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 had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.

12.2       Pharmacodynamics

Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like (CT-L) activity when measured in blood 1 hour after the first dose. Doses of carfilzomib ≥ 15 mg/m2 with or without lenalidomide and dexamethasone induced a ≥ 80% inhibition of the CT-L activity of the proteasome. In addition, carfilzomib, 20 mg/m2 intravenously as a single agent, resulted in a mean inhibition of the low molecular mass polypeptide 2 (LMP2) and multicatalytic endopeptidase complex-like 1 (MECL1) subunits of the proteasome ranging from 26% to 32% and 41% to 49%, respectively.  Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing.

12.3       Pharmacokinetics

Carfilzomib at doses between 20 mg/m2 and 70 mg/m2 administered as a 30-minute infusion resulted in dose-dependent increases in maximum plasma concentrations (Cmax) and area under the curve over time to infinity (AUCinf) in patients with multiple myeloma.  A dose-dependent increase in Cmax and AUCinf was also observed between carfilzomib 20 mg/m2 and 56 mg/m2 as a 2- to 10-minute infusion in patients with relapsed or refractory multiple myeloma.  A 30-minute infusion resulted in a similar AUCinf, but 2- to 3-fold lower Cmax than that observed with a 2- to 10-minute infusion at the same dose.  There was no evidence of carfilzomib accumulation following repeated administration of carfilzomib 70 mg/m2 as a 30-minute once weekly infusion or 15 and 20 mg/m2 as a 2- to 10-minute twice weekly infusion.

Table 17 lists the estimated mean average daily area under the curve in the first cycle (AUCC1,avg), average daily area under the curve at steady-state (AUCss) and Cmax at the highest dose in the first cycle (Cmax,C1) for the different dosing regimens.

Distribution

The mean steady-state volume of distribution of a 20 mg/m2 dose of carfilzomib was 28 L. Carfilzomib is 97% bound to human plasma proteins over the concentration range of 0.4 to 4 micromolar in vitro.

Elimination

Carfilzomib has a half-life of ≤ 1 hour on Day 1 of Cycle 1 following intravenous doses ≥ 15 mg/m2. The half-life was similar when administered either as a 30-minute infusion or a 2- to 10-minute infusion. The systemic clearance ranged from 151 to 263 L/hour.

Metabolism

Carfilzomib is rapidly metabolized by peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism. Cytochrome P450 (CYP)-mediated mechanisms contribute a minor role in overall carfilzomib metabolism.

Excretion

Approximately 25% of the administered dose of carfilzomib was excreted in urine as metabolites in 24 hours. Urinary and fecal excretion of the parent compound was negligible (0.3% of total dose).

Specific Populations

Age (35-89 years), sex, race or ethnicity (80% White, 11% Black, 6% Asians, 3% Hispanics), and mild to severe renal impairment (creatinine clearance 15-89 mL/min) did not have clinically meaningful effects on the pharmacokinetics of carfilzomib.

Patients with Hepatic Impairment

Compared to patients with normal hepatic function, patients with mild (total bilirubin 1 to 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) and moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment had approximately 50% higher carfilzomib AUC. The pharmacokinetics of carfilzomib has not been evaluated in patients with severe hepatic impairment (total bilirubin > 3 × ULN and any AST).

Patients with Renal Impairment

Relative to patients with normal renal function, ESRD patients on hemodialysis showed 33% higher carfilzomib AUC. Since hemodialysis clearance of Kyprolis concentrations has not been studied, the drug should be administered after the hemodialysis procedure.

Drug Interaction Studies

Clinical Studies

Effect of Carfilzomib on Sensitive CYP3A Substrate

Midazolam (a sensitive CYP3A substrate) pharmacokinetics was not affected by concomitant administration of carfilzomib.

In Vitro Studies

Effect of Carfilzomib on Cytochrome P450 (CYP) Enzymes

Carfilzomib showed direct and time-dependent inhibition of CYP3A but did not induce CYP1A2 and CYP3A4 in vitro.

Effect of Transporters on Carfilzomib

Carfilzomib is a P-glycoprotein (P-gp) substrate in vitro.

Effect of Carfilzomib on Transporters

Carfilzomib inhibits P-gp in vitro. However, given that Kyprolis is administered intravenously and is extensively metabolized, the pharmacokinetics of Kyprolis is unlikely to be affected by P-gp inhibitors or inducers.

13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with carfilzomib.

Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay.

Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies.

13.2       Animal Toxicology and/or Pharmacology

Cardiovascular Toxicity:  Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on BSA) experienced hypotension, increased heart rate, and increased serum levels of troponin-T.

Chronic Administration: Repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on BSA. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on BSA.

14.1       In Combination with Lenalidomide and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma

ASPIRE (NCT01080391)

ASPIRE was a randomized, open-label, multicenter superiority trial which evaluated the combination of Kyprolis with lenalidomide and dexamethasone (KRd) versus lenalidomide and dexamethasone alone (Rd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 lines of therapy (A line of therapy is a planned course of treatment [including sequential induction, transplantation, consolidation, and/or maintenance] without an interruption for lack of efficacy, such as for relapse or progressive disease). Patients who had the following were excluded from the trial: refractory to bortezomib in the most recent regimen, refractory to lenalidomide and dexamethasone in the most recent regimen, not responding to any prior regimen, creatinine clearance < 50 mL/min, ALT/AST > 3.5 × ULN and bilirubin > 2 × ULN, New York Heart Association Class III to IV congestive heart failure, or myocardial infarction within the last 4 months. In the KRd arm, Kyprolis was evaluated at a starting dose of 20 mg/m2, which was increased to 27 mg/m2 on Cycle 1, Day 8 onward.  Kyprolis was administered as a 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle for Cycle 1 through 12.  Kyprolis was dosed on Days 1, 2, 15, and 16 of each 28-day cycle from Cycle 13 through 18.  Dexamethasone 40 mg was administered orally or intravenously on Days 1, 8, 15 and 22 of each cycle.  Lenalidomide was given 25 mg orally on Days 1 to 21 of each 28-day cycle.  The Rd treatment arm had the same regimen for lenalidomide and dexamethasone as the KRd treatment arm. Kyprolis was administered for a maximum of 18 cycles unless discontinued early for disease progression or unacceptable toxicity. Lenalidomide and dexamethasone administration could continue until progression or unacceptable toxicity.  Concurrent use of thromboprophylaxis and a proton pump inhibitor were required for both arms, and antiviral prophylaxis was required for the KRd arm.

The 792 patients in ASPIRE were randomized 1:1 to the KRd or Rd arm. The demographics and baseline characteristics were well-balanced between the two arms (see Table 18). Only 53% of the patients had testing for genetic mutations; a high-risk genetic mutation was identified for 12% of patients in the KRd arm and in 13% in the Rd arm.

Patients in the KRd arm demonstrated improved PFS compared with those in the Rd arm (HR = 0.69, with 2-sided P-value = 0.0001) as determined using standard International Myeloma Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria by an Independent Review Committee (IRC).

The median PFS was 26.3 months in the KRd arm versus 17.6 months in the Rd arm (see Table 19 and Figure 1).

A pre-planned overall survival (OS) analysis was performed after 246 deaths in the KRd arm and 267 deaths in the Rd arm. The median follow-up was approximately 67 months. A statistically significant advantage in OS was observed in patients in the KRd arm compared to patients in the Rd arm (see Table 19 and Figure 2).

The median duration of response (DOR) was 28.6 months (95% CI:  24.9, 31.3) for the 345 patients achieving a response in the KRd arm and 21.2 months (95% CI:  16.7, 25.8) for the 264 patients achieving a response in the Rd arm. The median time to response was 1 month (range 1 to 14 months) in the KRd arm and 1 month (range 1 to 16 months) in the Rd arm.

Figure 1: Kaplan-Meier Curve of Progression-Free Survival in ASPIRE

CI = confidence interval; EBMT = European Blood and Marrow Transplantation; HR = hazard ratio; IMWG = International Myeloma Working Group; KRd = Kyprolis, lenalidomide, and dexamethasone; mo = months; PFS = progression-free survival; Rd = lenalidomide and dexamethasone arm Note: The response and PD outcomes were determined using standard objective IMWG/EBMT response criteria.

Figure 2: Kaplan-Meier Curve of Overall Survival in ASPIRE

CI = confidence interval; HR = hazard ratio; KRd = Kyprolis, lenalidomide, and dexamethasone; mo = month; OS = overall survival; Rd = lenalidomide and dexamethasone arm

14.2       In Combination with Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma

ENDEAVOR (NCT01568866)

ENDEAVOR was a randomized, open-label, multicenter superiority trial of Kyprolis plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 lines of therapy. A total of 929 patients were enrolled and randomized (464 in the Kd arm; 465 in the Vd arm). Randomization was stratified by prior proteasome inhibitor therapy (yes versus no), prior lines of therapy (1 versus 2 or 3), current International Staging System stage (1 versus 2 or 3), and planned route of bortezomib administration. Patients were excluded if they had less than PR to all prior regimens; creatinine clearance < 15 mL/min; hepatic transaminases ≥ 3 × ULN; or left-ventricular ejection fraction < 40% or other significant cardiac conditions.  This trial evaluated Kyprolis at a starting dose of 20 mg/m2, which was increased to 56 mg/m2 on Cycle 1, Day 8 onward.  Kyprolis was administered twice weekly as a 30-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle.  Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle.  In the Vd arm, bortezomib was dosed at 1.3 mg/m2 intravenously or subcutaneously on Days 1, 4, 8, and 11 of a 21-day cycle, and dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle. Concurrent use of thromboprophylaxis was optional, and prophylaxis with an antiviral agent and proton pump inhibitor was required.  Of the 465 patients in the Vd arm, 381 received bortezomib subcutaneously. Treatment continued until disease progression or unacceptable toxicity.

The demographics and baseline characteristics are summarized in Table 20.

The efficacy of Kyprolis was evaluated by PFS as determined by an IRC using IMWG response criteria. The trial showed a median PFS of 18.7 months in the Kd arm versus 9.4 months in the Vd arm (see Table 21 and Figure 3).

Figure 3: Kaplan-Meier Plot of Progression-Free Survival in ENDEAVOR

CI = confidence interval; HR = hazard ratio; Kd = Kyprolis plus dexamethasone; mo = months; PFS = progression-free survival; Vd = bortezomib and dexamethasone

Other endpoints included OS and overall response rate (ORR).  

A pre-planned OS analysis was performed after 189 deaths in the Kd arm and 209 deaths in the Vd arm. The median follow-up was approximately 37 months. A significantly longer OS was observed in patients in the Kd arm compared to patients in the Vd arm (HR = 0.79; 95% CI: 0.65, 0.96; P-value = 0.01) (see Table 21 and Figure 4).

ORR was 77% for patients in the Kd arm and 63% for patients in the Vd arm (see Table 21).

Figure 4: Kaplan-Meier Plot of Overall Survival in ENDEAVOR

CI = confidence interval; HR = hazard ratio; Kd = Kyprolis plus dexamethasone; mo = month; OS = overall survival; Vd = bortezomib and dexamethasone

The median DOR in subjects achieving PR or better was 21.3 months (95% CI:  21.3, not estimable) in the Kd arm and 10.4 months (95% CI:  9.3, 13.8) in the Vd arm.  The median time to response was 1 month (range < 1 to 8 months) in both arms.

A.R.R.O.W. (NCT02412878)

A.R.R.O.W. was a randomized, open-label, multicenter superiority trial of Kyprolis plus dexamethasone (Kd) once weekly (20/70 mg/m2) versus Kd twice weekly (20/27 mg/m2) in patients with relapsed and refractory multiple myeloma who had received 2 to 3 prior lines of therapy. Patients were excluded if they had less than PR to at least one prior line; creatinine clearance < 30 mL/min; hepatic transaminases ≥ 3 × ULN; or left-ventricular ejection fraction < 40% or other significant cardiac conditions. A total of 478 patients were enrolled and randomized (240 in 20/70 mg/m2 arm; 238 in 20/27 mg/m2 arm).  Randomization was stratified by current International Staging System stage (stage 1 versus stages 2 or 3), refractory to bortezomib treatment (yes versus no), and age (< 65 versus ≥ 65 years). Arm 1 of this trial evaluated Kyprolis at a starting dose of 20 mg/m2, which was increased to 70 mg/m2 on Cycle 1, Day 8 onward. Arm 1 Kyprolis was administered once weekly as a 30-minute infusion on Days 1, 8 and 15, of each 28-day cycle. Arm 2 of this trial evaluated Kyprolis at a starting dose of 20 mg/m2, which was increased to 27 mg/m2 on Cycle 1, Day 8 onward. Arm 2 Kyprolis was administered twice weekly as a 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. In both regimens, dexamethasone 40 mg was administered orally or intravenously on Days 1, 8, 15 for all cycles and on Day 22 for cycles 1 to 9 only. Concurrent use of thromboprophylaxis was optional, prophylaxis with an antiviral agent was recommended, and prophylaxis with a proton pump inhibitor was required.  Treatment continued until disease progression or unacceptable toxicity.

The demographics and baseline characteristics are summarized in Table 22.

The efficacy of Kyprolis was evaluated by PFS using IMWG response criteria. The trial showed a median PFS of 11.2 months in the once weekly Kd 20/70 mg/m2 arm versus 7.6 months in the twice weekly Kd 20/27 mg/m2 arm (see Table 23 and Figure 5).

Figure 5: Kaplan-Meier Plot of Progression-Free Survival in A.R.R.O.W.

CI = confidence interval; HR = hazard ratio; Kd = Kyprolis plus dexamethasone; PFS = progression-free survival

Other endpoints included ORR. ORR was 62.9% for patients in the Kd 20/70 mg/m2 once weekly arm and 40.8% for patients in the Kd 20/27 mg/m2 twice weekly arm (see Table 23).

The median DOR in subjects achieving PR or better was 15 months (95% CI: 12.2, not estimable) in the Kd 20/70 mg/m2 arm and 13.8 months (95% CI: 9.5, not estimable) in the Kd 20/27 mg/m2 arm. The median time to response was 1.1 months in the Kd 20/70 mg/m2 arm and 1.9 months in the Kd 20/27 mg/m2 arm.

Kyprolis is not approved for twice weekly 20/27 mg/m2 administration in combination with dexamethasone alone.

14.3       Monotherapy for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma 

Study PX-171-007 (NCT00531284)

Study PX-171-007 was a multicenter, open-label, dose escalation, single-arm trial that evaluated the safety of carfilzomib monotherapy as a 30-minute infusion in patients with relapsed or refractory multiple myeloma after 2 or more lines of therapy. Patients were excluded if they had a creatinine clearance < 20 mL/min; ALT ≥ 3 × upper limit of normal (ULN), bilirubin ≥ 1.5 × ULN; New York Heart Association Class III or IV congestive heart failure; or other significant cardiac conditions. A total of 24 subjects with multiple myeloma were enrolled at the maximum tolerated dose level of 20/56 mg/m2. Carfilzomib was administered twice weekly for 3 consecutive weeks (Days 1, 2, 8, 9, 15, and 16) of a 28-day cycle. In Cycle 13 onward, the Day 8 and 9 carfilzomib doses could be omitted. Patients received carfilzomib at a starting dose of 20 mg/m2 on Days 1 and 2 of Cycle 1, which was increased to 56 mg/m2 for all subsequent doses. Dexamethasone 8 mg orally or intravenously was required prior to each carfilzomib dose in Cycle 1 and was optional in subsequent cycles. Treatment was continued until disease progression or unacceptable toxicity.

Efficacy was evaluated by ORR and DOR. ORR by investigator assessment was 50% (95% CI:  29, 71) per IMWG criteria (see Table 24). The median DOR in subjects who achieved a PR or better was 8.0 months (Range: 1.4, 32.5).

Study PX-171-003 A1 (NCT00511238)

Study PX-171-003 A1 was a single-arm, multicenter clinical trial of Kyprolis monotherapy by up to 10-minute infusion. Eligible patients were those with relapsed and refractory multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) and had ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. Patients were excluded from the trial if they were refractory to all prior therapies or had a total bilirubin ≥ 2 × ULN; creatinine clearance < 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last 6 months; peripheral neuropathy Grade 3 or 4, or peripheral neuropathy Grade 2 with pain; active infections requiring treatment; or pleural effusion.

Kyprolis was administered intravenously up to 10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients received 20 mg/m2 at each dose in Cycle 1, and 27 mg/m2 in subsequent cycles. Dexamethasone 4 mg orally or intravenously was administered prior to Kyprolis doses in the first and second cycles.

A total of 266 patients were enrolled. Baseline patient and disease characteristics are summarized in Table 25.

Efficacy was evaluated by ORR as determined by IRC assessment using IMWG criteria. The median number of cycles started was four. The ORR (PR or better) was 23% (95% CI:  18, 28) (see Table 26). The median DOR was 7.8 months (95% CI:  5.6, 9.2).

Study PX-171-004 Part 2 (NCT00530816)

Study PX-171-004 Part 2 was a single-arm, multicenter clinical trial of Kyprolis monotherapy by up to 10-minute infusion. Eligible patients were those with relapsed or refractory multiple myeloma who were bortezomib-naïve, had received one to three prior lines of therapy and had ≤ 25% response or progression during therapy or within 60 days after completion of therapy. Patients were excluded from the trial if they were refractory to standard first-line therapy or had a total bilirubin ≥ 2 × ULN; creatinine clearance < 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last 6 months; active infections requiring treatment; or pleural effusion.

Kyprolis was administered intravenously up to 10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients received 20 mg/m2 at each dose in Cycle 1, and 27 mg/m2 in subsequent cycles. Dexamethasone 4 mg orally or intravenously was administered prior to Kyprolis doses in the first and second cycles.

A total of 70 patients were treated with this 20/27 mg/m2 regimen. Baseline patient and disease characteristics are summarized in Table 27.

Table 27:  Demographics and Baseline Characteristics in Study PX-171-004 Part 2 (20/27 mg/m2 Monotherapy Regimen for Relapsed or Refractory Multiple Myeloma)

Efficacy was evaluated by ORR as determined by IRC assessment using IMWG criteria. The median number of cycles started was seven. The ORR (PR or better) was 50% (95% CI:  38, 62) (see Table 28). The median DOR was not reached.

16.1       How Supplied

Kyprolis (carfilzomib) is supplied as:

• An individually packaged single-dose vial containing 10 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-103-01.
  
• An individually packaged single-dose vial containing 30 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-102-01. 
  
• An individually packaged single-dose vial containing 60 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-101-01.

16.2       Storage and Handling

Unopened vials should be stored refrigerated 2°C to 8°C (36°F to 46°F). Retain in original package to protect from light.