Kyprolis

Carfilzomib.

Each 60 mg vial contains 60 mg of carfilzomib, 3000 mg sulfobutylether beta-cyclodextrin, 57.7 mg citric acid, and sodium hydroxide for pH adjustment (target pH 3.5).
Kyprolis for injection, for intravenous use is a sterile, white to off-white lyophilized powder in a single-dose vial.
Carfilzomib is a proteasome inhibitor.
The chemical name for carfilzomib is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)- 1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide.
Carfilzomib is a crystalline substance with a molecular weight of 719.9. The molecular formula is C₄₀H₅₇N₅O₇. Carfilzomib is practically insoluble in water and very slightly soluble in acidic conditions.

Pharmacology: 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.
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.
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 (C_max) and area under the curve over time to infinity (AUC_0-INF) in patients with multiple myeloma. A dose dependent increase in C_max and AUC_0-INF 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 AUC_0-INF, but 2- to 3-fold lower C_max 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 1 lists the estimated mean average daily area under the curve in the first cycle (AUC_C1,avg), average daily area under the curve at steady-state (AUC_ss) and C_max at the highest dose in the first cycle (C_max,C1) for the different dosing regimens. (See Table 1.)

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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. 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.
Toxicology: Non-Clinical Toxicology: 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.
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.
Clinical Studies: In Combination with Lenalidomide and Dexamethasone for Relapsed or Refractory Multiple Myeloma: ASPIRE (NCT01080391): ASPIRE was a randomized, open-label, multicenter 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 2). 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. (See Table 2.)

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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 3 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 3 and Figure 2). (See Table 3.)

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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. (See Figures 1 and 2.)

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In Combination with Dexamethasone for Relapsed or Refractory Multiple Myeloma: The efficacy of Kyprolis in combination with dexamethasone was evaluated in two open-label randomized trials (ENDEAVOR and A.R.R.O.W).
ENDEAVOR (NCT01568866): ENDEAVOR was a randomized, open-label, multicenter superiority trial of Kyprolis and dexamethasone (Kd) versus bortezomib and 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 4. (See Table 4.)

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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 5 and Figure 3). (See Figure 3.)

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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). Results are provided in Table 5 and Figure 4. (See Table 5 and Figure 4).

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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 6. (See Table 6.)

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The efficacy of Kyprolis was evaluated by PFS using IMWG response criteria. Efficacy results are approved in Table 7 and Figure 5. (See Table 7 and Figure 5.)

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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.
In combination with Intravenous Daratumumab and Dexamethasone for Relapsed or Refractory Multiple Myeloma: The efficacy of Kyprolis in combination with daratumumab and dexamethasone (DKd) was evaluated in two open-label clinical trials (CANDOR and EQUULEUS).
CANDOR (NCT03158688): CANDOR was a randomized, open-label, multicenter trial which evaluated the combination of Kyprolis 20/56 mg/m² twice weekly with intravenous daratumumab and dexamethasone (DKd) versus Kyprolis 20/56 mg/m² twice weekly and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy. Patients who had the following were excluded from the trial: known moderate or severe persistent asthma within the past 2 years, known chronic obstructive pulmonary disease (COPD) with a FEV1 < 50% of predicted normal, and active congestive heart failure. Randomization was stratified by the ISS (stage 1 or 2 vs stage 3) at screening, prior proteasome inhibitor exposure (yes vs no), number of prior lines of therapy (1 vs ≥ 2), or prior cluster differentiation antigen 38 (CD38) antibody therapy (yes vs no).
Kyprolis was administered intravenously over 30 minutes at a dose of 20 mg/m² in Cycle 1 on Days 1 and 2; at a dose of 56 mg/m² in Cycle 1 on Days 8, 9, 15 and 16; and on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle thereafter. Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15 and 16 and then 40 mg orally or intravenously on Day 22 of each 28-day cycle. In the DKd arm, daratumumab was administered intravenously at a dose of 8 mg/kg in Cycle 1 on Days 1 and 2. Thereafter, daratumumab was administered intravenously at a dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, 8 and 15 and 22 of Cycle 2; Days 1 and 15 of Cycles 3 to 6; and Day 1 for the remaining cycles or until disease progression. For patients >75 years on a reduced dexamethasone dose of 20 mg, the entire 20 mg dose was given as a daratumumab pre-infusion medication on days when daratumumab was administered. Dosing of dexamethasone was otherwise split across days when Kyprolis was administered in both study arms. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 466 patients were randomized; 312 to the DKd arm and 154 to the Kd arm. The demographics and baseline characteristics are summarized in Table 8. (See Table 8.)

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Efficacy was assessed by an IRC evaluation of PFS using the IMWG response criteria. Efficacy results are provided in Table 9 and Figure 6. The median duration of response has not been reached for the DKd arm and was 16.6 months (13.9, NE) for the Kd arm. The median (min, max) time to response was 1.0 (1, 14) months for the DKd arm and 1.0 (1, 10) months for the Kd arm. (See Figure 6 and Table 9.)

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EQUULEUS (NCT01998971): EQUULEUS was an open-label, multi-cohort trial which evaluated the combination of Kyprolis with intravenous daratumumab and dexamethasone in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy. Patients who had the following were excluded from the trial: known moderate or severe persistent asthma within the past 2 years, known chronic obstructive pulmonary disease (COPD) with a FEV1 < 50% of predicted normal, or active congestive heart failure (defined as New York Heart Association Class III-IV).
Kyprolis was administered intravenously over 30 minutes once weekly at a dose of 20 mg/m² on Cycle 1 Day 1 and escalated to a dose of 70 mg/m² on Cycle 1, Days 8 and 15; and on Days 1, 8, and 15 of each 28-day cycle. Ten patients were administered daratumumab at a dose of 16 mg/kg intravenously on Cycle 1, Day 1 and the remaining patients were administered daratumumab at a dose of 8 mg/kg intravenously on Cycle 1, Days 1 and 2. Thereafter, daratumumab was administered intravenously at a dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, 8, 15 and 22 of Cycle 2; Days 1 and 15 of Cycles 3 to 6; and then Day 1 for the remaining cycles of each 28-day cycle. In Cycles 1 and 2, dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15, 16, 22 and 23; in cycles 3 to 6, dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 15 and 16 and at a dose of 40 mg on Day 8 and 22; and in cycles 7 and thereafter, dexamethasone 20 mg was administered orally or intravenously on Days 1 and 2 and at a dose of 40 mg on Days 8, 15, and 22. For patients > 75 years of age, dexamethasone 20 mg was administered orally or intravenously weekly after the first week. Treatment continued until disease progression or unacceptable toxicity.
The EQUULEUS trial enrolled 85 patients. The demographics and baseline characteristics are summarized in Table 10. (See Table 10.)

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Efficacy results were based on overall response rate using IMWG criteria. Efficacy results are provided in Table 11. The median time to response was 0.95 months (range: 0.9, 14.3). The median duration of response was 28 months (95% CI: 20.5, not estimable). (See Table 11.)

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Relapsed or Refractory Multiple Myeloma: Kyprolis is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with: Lenalidomide and dexamethasone; or Dexamethasone; or Daratumumab and dexamethasone.

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. Consider hydration with 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 Cardiac Toxicities and Tumor Lysis Syndrome under Precautions].
Electrolyte Monitoring: Monitor serum potassium levels regularly during treatment with Kyprolis [see Clinical Trials Experience under Adverse Reactions].
Premedications and Concomitant Medications: Premedicate with dexamethasone administered as part of the combination therapy [see Recommended Dosage as follows]. 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-related reactions [see Infusion-Related Reactions under Precautions]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.
Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies [see Venous Thrombosis under Precautions].
Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation [see Clinical Trials Experience under Adverse Reactions].
Dose Calculation: For patients with body surface area (BSA) of 2.2 m² or less, calculate the Kyprolis dose using actual BSA. Dose adjustments do not need to be made for weight changes of 20% or less.
For patients with a BSA greater than 2.2 m², calculate the Kyprolis dose using a BSA of 2.2 m².
Recommended Dosage: Kyprolis in Combination with Lenalidomide and Dexamethasone: Administer Kyprolis intravenously as a 10 minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle in combination with lenalidomide and dexamethasone until Cycle 12 as shown in Table 12 [see Pharmacology: Clinical Studies: In Combination with Lenalidomide and Dexamethasone for Relapse or Refractory Multiple Myeloma under Actions]. The recommended starting dose of Kyprolis is 20 mg/m² on Cycle 1, Days 1 and 2. If tolerated, escalate the dose to 27 mg/m² on Cycle 1, Day 8. From Cycle 13, administer Kyprolis on Days 1, 2, 15, 16 until Cycle 18. Discontinue Kyprolis after Cycle 18. Continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity occurs. Refer to the Prescribing Information for lenalidomide and dexamethasone for additional dosage information. (See Table 12.)

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Kyprolis in Combination with Dexamethasone: Twice weekly 20/56 mg/m² regimen by 30-minute infusion: Administer Kyprolis intravenously as a 30-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle in combination with dexamethasone until disease progression or unacceptable toxicity as shown in Table 13 [see Pharmacology: Clinical Studies: In Combination with Dexamethasone for Relapsed or Refractory Multiple Myeloma under Actions]. The recommended starting dose of Kyprolis is 20 mg/m² on Cycle 1, Days 1 and 2. If tolerated, escalate the dose to 56 mg/m² on Cycle 1, Day 8. Administer dexamethasone 30 minutes to 4 hours before Kyprolis. Refer to the Prescribing Information for dexamethasone for additional dosage information. (See Table 13.)

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Once weekly 20/70 mg/m² regimen by 30-minute infusion: Administer Kyprolis intravenously as a 30-minute infusion on Days 1, 8, and 15 of each 28-day cycle in combination with dexamethasone until disease progression or unacceptable toxicity as shown in Table 14 [see Pharmacology: Clinical Studies: In Combination with Dexamethasone for Relapsed or Refractory Multiple Myeloma under Actions]. The recommended starting dose of Kyprolis is 20 mg/m² on Cycle 1, Day 1. If tolerated, escalate the dose to 70 mg/m² on Cycle 1, Day 8. Administer dexamethasone 30 minutes to 4 hours before Kyprolis. Refer to Prescribing Information for dexamethasone for additional dosage information. (See Table 14.)

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Kyprolis in Combination with Intravenous Daratumumab and Dexamethasone: Twice weekly 20/56 mg/m² regimen by 30-minute infusion: Administer Kyprolis intravenously as a 30-minute infusion on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle in combination with intravenous daratumumab and dexamethasone until disease progression or unacceptable toxicity as shown in Table 15 [see Pharmacology: Clinical Studies: In Combination with Intravenous Daratumumab and Dexamethasone for Relapsed or Refractory Multiple Myeloma under Actions]. The recommended starting dose of Kyprolis is 20 mg/m² on Cycle 1, Days 1 and 2. If tolerated, escalate the dose to 56 mg/m² on Cycle 1, Day 8 and thereafter. Administer dexamethasone 30 minutes to 4 hours before Kyprolis and 1 to 3 hours before intravenous daratumumab. Refer to the Prescribing Information for intravenous daratumumab and dexamethasone for additional dosage information. (See Table 15.)

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Once weekly 20/70 mg/m² regimen by 30-minute infusion: Administer Kyprolis intravenously as a 30-minute infusion on Days 1, 8 and 15 of each 28-day cycle in combination with intravenous daratumumab and dexamethasone until disease progression or unacceptable toxicity as shown in Table 15 [see Pharmacology: Clinical Studies: In Combination with Intravenous Daratumumab and Dexamethasone for Relapsed or Refractory Multiple Myeloma under Actions]. The recommended starting dose of Kyprolis is 20 mg/m² on Cycle 1, Day 1. If tolerated, escalate the dose to 70 mg/m² on Cycle 1, Day 8 and thereafter. Administer dexamethasone 30 minutes to 4 hours before Kyprolis and 1 to 3 hours before intravenous daratumumab. Refer to the Prescribing Information for intravenous daratumumab and dexamethasone for additional dosage information. (See Table 16.)

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Dosage Modifications for Adverse Reactions: Recommended actions and dosage modifications for Kyprolis are presented in Table 17. Dose level reductions are presented in Table 18. See the lenalidomide, intravenous daratumumab, and dexamethasone Prescribing Information respectively for recommended dosage modifications associated with each product. (See Table 17 and Table 18.)

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Dosage Modifications for Hepatic Impairment: For 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, reduce the dose of Kyprolis by 25% [see Hepatic Impairment under Precautions, Pharmacology: Pharmacokinetics under Actions].
Recommended Dosage for End Stage Renal Disease: For patients with end stage renal disease who are on hemodialysis, administer Kyprolis after the hemodialysis procedure.
Preparation and Administration: Kyprolis vials contain no antimicrobial preservatives and are intended for single-dose only. 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.
3. Aseptically reconstitute each Kyprolis vial only with Sterile Water for Injection, USP using the volumes described in Table 19. 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. (See Table 19.)

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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. Administer Kyprolis directly by intravenous infusion or 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 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).
9. Flush the intravenous administration line with normal saline or 5% Dextrose Injection, USP immediately before and after Kyprolis administration.
10. Do not mix Kyprolis with or administer as an infusion with other medicinal products.
The stabilities of reconstituted Kyprolis under various temperature and container conditions are shown in Table 20. (See Table 20.)

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Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia, and lymphopenia has been reported following a dose of 200 mg of Kyprolis administered in error.
There is no known specific antidote for Kyprolis overdosage. In the event of overdose, monitor patients for adverse reactions and provide supportive care as appropriate.

Hypersensitivity to the active substance or to any of the excipients [see Description].
Women who are breast-feeding [see Lactation under Use of Pregnancy & Lactation].
As Kyprolis is administered in combination with other medicinal products, refer to their summaries of product characteristics product insert for additional contraindications.

Cardiac Toxicities: New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Some events occurred in patients with normal baseline ventricular function. 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% and that of arrythmias was 8% (majority of which were atrial fibrillation and sinus tachycardia) [see Clinical Trials Experience under Adverse Reactions].
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 reactions until recovery and consider whether to restart Kyprolis at 1 dose level reduction based on a benefit/risk assessment [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure [see Administration Precautions under Dosage & Administration].
In patients ≥75 years of age, the risk of cardiac failure is increased compared to younger patients. The risk of cardiac failure is also increased in Asian patients. 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; for these patients, complete 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 Elderly as follows].
Acute Renal Failure: Cases of acute renal failure have occurred in patients receiving Kyprolis. Some of these events have been fatal. Renal insufficiency (including renal failure) has occurred in approximately 9% of patients who received Kyprolis. 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 Modifications for Adverse Reactions under Dosage & Administration].
Tumor Lysis Syndrome: Cases of 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.Administer oral and intravenous fluids before administration of Kyprolis in Cycle 1 and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for TLS during treatment and manage promptly including interruption of Kyprolis until TLS is resolved [see Administration Precautions under Dosage & Administration].
Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute respiratory failure have occurred in approximately 2% of patients who received Kyprolis. In addition, acute diffuse infiltrative pulmonary disease, such as pneumonitis and interstitial lung disease, occurred in approximately 2% of patients who received Kyprolis. Some events were fatal.
In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.
Pulmonary Hypertension: Pulmonary arterial hypertension was reported in approximately 2% of patients who received Kyprolis, with Grade 3 or greater in less than 1%.
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.
Dyspnea: Dyspnea was reported in 25% of patients treated with Kyprolis, with Grade 3 or greater in 4%.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 Cardiac Toxicities and Pulmonary Toxicity as previously mentioned and Clinical Trials Experience under Adverse Reactions).
Hypertension: Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. In ASPIRE, the incidence of hypertension events was 17% in the KRd arm versus 9% in the Rd arm. In ENDEAVOR, the incidence of hypertension events was 34% in the Kd arm versus 11% in the Vd arm. In CANDOR, the incidence of hypertension events was 31% in the DKd arm versus 28% in the Kd arm. Some of these events have been fatal.
Optimize blood pressure 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.
Venous Thrombosis: Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. In ASPIRE, 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 ENDEAVOR, the incidence of venous thromboembolic events in months 1-6 was 9% in the Kd arm versus 2% in the Vd arm.
Provide thromboprophylaxis for patients being treated with Kyprolis in combination with lenalidomide and dexamethasone, with dexamethasone; or with intravenous daratumumab and dexamethasone. Select the thromboprophylaxis regimen based on the patient's underlying risks.
For patients using oral contraceptives or hormonal contraception associated with a risk of thrombosis, consider non-hormonal contraception during treatment when Kyprolis is administered in combination [see Females and Males of Reproductive Potential under Use of Pregnancy & Lactation].
Infusion-Related Reactions: Infusion-related 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-related reactions [see Administration Precautions and Recommended Dosage under Dosage & Administration, Clinical Trials Experience under Adverse Reactions].
Haemorrhage: Fatal or serious cases of hemorrhage have been reported in patients treated with Kyprolis [see Clinical Trials Experience under Adverse Reactions]. 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 Modifications for Adverse under Dosage & Administration].
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 Clinical Trials Experience under Adverse Reactions]. Thrombocytopenia was reported in approximately 32% of patients in clinical trials with Kyprolis. Hemorrhage may occur [see Clinical Trials Experience under Adverse Reactions, Haemorrhage as previously mentioned].
Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (2%) during treatment with Kyprolis. Kyprolis can cause increased serum transaminases [see Clinical Trials Experience under Adverse Reactions].
Monitor liver enzymes regularly, regardless of baseline values. Reduce or withhold dose as appropriate [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
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.
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.
Progressive Multifocal Leukoencephalopathy: Progressive multifocal leukoencephalopathy (PML), which can be fatal, has been reported with Kyprolis. In addition to Kyprolis, other possible contributary factors include prior or concurrent immunosuppressive therapy that may cause immunosuppression.
Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue Kyprolis and initiate evaluation for PML including neurology consultation.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients: In CLARION, 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.
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.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Kyprolis and for 6 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the final dose [see Use Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation), Pharmacology: Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions].
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. A recommended dosage of Kyprolis has not been established for patients with severe hepatic impairment (total bilirubin > 3 × ULN and any AST) [see Dosage Modifications for Hepatic Impairment under Dosage & Administration, Pharmacology: Pharmacokinetics under Actions].
The incidence of serious adverse reactions 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 Hepatic Toxicity and Hepatic Failure under Precautions, Pharmacology: Pharmacokinetics under Actions].
Use in Children: The safety and effectiveness of Kyprolis in pediatric patients have not been established.
Use in Elderly: Of the 2,387 patients in clinical studies of Kyprolis, 51% were 65 years and older, while 14% were 75 years and older. The incidence of serious adverse reactions was 49% in patients < 65 years of age, 58% in patients 65 to 74 years of age, and 63% in patients ≥ 75 years of age. Of the 308 patients in CANDOR who received DKd, 47% of patients were 65 years and older, while 9% were 75 years and older. Fatal adverse reactions in the DKd arm of CANDOR occurred in 6% of patients <65 years of age, 14% of patients between 65 to 74 years of age, and 14% of patients ≥ 75 years of age [see Clinical Trials Experience under Adverse Reactions]. No overall differences ineffectiveness were observed between older and younger patients.

Pregnancy: Risk Summary: Kyprolis can cause fetal harm based on findings from animal studies and its mechanism of action [see Pharmacology: Mechanism of Action under Actions]. There are no available data on Kyprolis use in pregnant women to evaluate for drug-associated risks. Kyprolis caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (see Data as follows). 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 andan 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.
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 of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Kyprolis and for 2 weeks after treatment.
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 Pregnancy as previously mentioned].
Pregnancy Testing: Conduct pregnancy testing on females of reproductive potential prior to initiating Kyprolis treatment.
Contraception: Females: Advise females of reproductive potential to 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 Pharmacology: Mechanism of Action under Actions and Pharmacology: Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions]. There are no data on the effect of Kyprolis on human fertility.

The following clinically significant adverse reactions are described in other sections of the monographs: Cardiac Toxicities [see Cardiac Toxicities under Precautions].
Acute Renal Failure [see Acute Renal Failure under Precautions].
Tumor Lysis Syndrome [see Tumor Lysis Syndrome under Precautions].
Pulmonary Toxicity [see Pulmonary Toxicity under Precautions].
Pulmonary Hypertension [see Pulmonary Hypertension under Precautions].
Dyspnea [see Dyspnea under Precautions].
Hypertension [see Hypertension under Precautions].
Venous Thrombosis [see Venous Thrombosis under Precautions].
Infusion-Related Reactions [see Infusion-Related Reactions under Precautions].
Hemorrhage [see Hemorrhage under Precautions].
Thrombocytopenia [see Thrombocytopenia under Precautions].
Hepatic Toxicity and Hepatic Failure [see Hepatic Toxicity and Hepatic Failure under Precautions].
Thrombotic Microangiopathy [see Thrombotic Microangiopathy under Precautions].
Posterior Reversible Encephalopathy Syndrome [see Posterior Reversible Encephalopathy Syndrome under Precautions].
Progressive Multifocal Leukoencephalopathy [see Progressive Multifocal Leukoencephalopathy under Precautions].
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients [see Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients under Precautions].
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.
The pooled safety population described previously in Precautions reflect exposure to Kyprolis in 1789 patients administered in combination with other drugs in ASPIRE, ENDEAVOR, A.R.R.O.W., and CANDOR. The most common adverse reactions occuring in at least 20% of patients who received Kyprolis in combination were anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia.
Kyprolis in Combination with Lenalidomide and Dexamethasone: The safety of Kyprolis 20/27 mg/m² twice weekly in combination with lenalidomide and dexamethasone (KRd) was evaluated in ASPIRE [Pharmacology: Clinical Studies: In Combination with Lenalidomide and Dexamethasone for Relapsed or Refractory Multiple Myeloma under Actions]. 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 reactions within 30 days of the last dose af any Rd therapy. The most frequent 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 frequent 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%).
Discontinuation due to any adverse reactions 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.
Table 21 summarizes the adverse reactions in the first 12 cycles in ASPIRE. (See Table 21.)

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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.
Table 22 describes Grade 3-4 laboratory abnormalities reported in ASPIRE. (See Table 22.)

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Kyprolis in Combination with Dexamethasone: The safety of Kyprolis in combination with dexamethasone was evaluated in two open-label, randomized trials (ENDEAVOR and A.R.R.O.W.).
ENDEAVOR: The safety of Kyprolis 20/56 mg/m² twice weekly in combination with dexamethasone (Kd) was evaluated in ENDEAVOR [Pharmacology: Clinical Studies: In Combination with Dexamethasone for Relapsed or Refractory Multiple Myeloma under Actions].
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 reactions 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 arms, pneumonia was the most frequently reported serious adverse reaction (8% versus 9%).
Discontinuation due to any adverse reaction occurred in 29% in the Kd arm versus 26% in the Vd arm. The most frequent adverse 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.
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 23. (See Table 23.)

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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.
Table 24 describes Grade 3-4 laboratory abnormalities reported at a rate of ≥ 10% in the Kd arm. (See Table 24.)

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A.R.R.O.W.: The safety of Kyprolis in combination with dexamethasone was evaluated in A.R.R.O.W. [Pharmacology: Clinical Studies under Actions]. Patients received treatment for a median duration of 38 weeks in the Kd 20/70 mg/m2 arm once weekly and 29.1 weeks in the Kd 20/27 mg/m² twice weekly arm. 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 arms, pneumonia was the most frequently reported serious adverse reaction (8% versus 7%).
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 frequent adverse 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.
Adverse reactions that occurred at a rate of 10% or greater in either Kd arm is presented in Table 25. (See Table 25.)

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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.
Kyprolis in Combination with Intravenous Daratumumab and Dexamethasone: The safety of Kyprolis in combination with intravenous daratumumab and dexamethasone was evaluated in two trials (CANDOR and EQUULEUS).
CANDOR: The safety of Kyprolis 20/56 mg/m² twice weekly in combination with intravenous daratumumab and dexamethasone (DKd) was evaluated in CANDOR [see Pharmacology: Clinical Studies: In Combination with Intravenous Daratumumab and Dexamethasone for Relapsed or Refractory Multiple Myeloma under Actions]. Patients received Kyprolis for a median duration of 58 weeks in the DKd arm and 40 weeks in the Kd arm.
Serious adverse reactions were reported in 56% of the patients in the DKd arm and 46% of the patients in the Kd arm. The most frequent serious adverse reactions reported in the DKd arm as compared with the Kd arm were pneumonia (14% versus 9%), pyrexia (4.2% versus 2.0%), influenza (3.9% versus 1.3%), sepsis (3.9% versus 1.3%), anemia (2.3% versus 0.7%), bronchitis (1.9% versus 0%) and diarrhea (1.6% versus 0%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 10% of 308 patients in the DKd arm compared with 5% of 153 patients in the Kd arm. The most frequent fatal adverse reaction (DKd versus Kd) was infection 4.5% versus 2.6%.
Permanent discontinuation due to an adverse reaction in patients who received Kyprolis occurred in 21% of patients in the DKd arm versus 22% in the Kd arm. The most frequent adverse reactions leading to discontinuation of Kyprolis were cardiac failure (1.9%) and fatigue (1.9%) in the DKd arm and cardiac failure (2.0%), hypertension (2.0%) and acute kidney injury (2.0%) in the Kd arm. Interruption of Kyprolis due to adverse reactions occurred in 71% of patients in DKd arm versus 63% in the Kd arm. Dose reduction of Kyprolis due to adverse reactions occurred in 25% of patients in DKd arm versus 20% in the Kd arm.
Infusion-related reactions that occurred following the first Kyprolis dose was 13% in the DKd arm versus 1% in the Kd arm.
Table 26 summarizes the adverse reactions in CANDOR. (See Table 26.)

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Adverse Reactions Occurring at a Frequency of < 15%: Blood and lymphatic system disorders: febrile neutropenia, thrombotic thrombocytopenic purpura.
Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiomyopathy, myocardial infarction, myocardial ischemia, tachycardia.
Eye disorders: cataract.
Gastrointestinal disorders: abdominal pain, gastrointestinal hemorrhage.
General disorders and administration site conditions: chest pain, malaise.
Infections: gastroenteritis, influenza, lung infection, nasopharyngitis, sepsis, septic shock, urinary tract infection, viral infection.
Investigations: alanine aminotransferase increased, blood creatinine increased, C-reactive protein increased, ejection fraction decreased.
Metabolism and nutrition disorders: dehydration, hyperglycemia, hyperkalemia, hypokalemia, hyponatremia, tumor lysis syndrome.
Musculoskeletal and connective tissue disorders: pain in extremity.
Nervous system disorders: cerebrovascular accident, intracranial hemorrhage, posterior reversible encephalopathy syndrome, peripheral neuropathy.
Psychiatric disorders: anxiety.
Renal and urinary disorders: acute kidney injury, renal failure, renal impairment.
Respiratory, thoracic and mediastinal disorders: acute respiratory failure, epistaxis, interstitial lung disease, pneumonitis, pulmonary embolism, pulmonary hypertension, pulmonary edema.
Skin and subcutaneous tissue disorders: rash.
Vascular disorders: deep vein thrombosis, hypertensive crisis.
EQUULEUS: The safety of Kyprolis 20/70 mg/m2 once weekly in combination with daratumumab and dexamethasone (DKd) was evaluated in EQUULEUS [see Pharmacology: Pharmacokinetics under Actions]. Patients received Kyprolis for a median duration of 66 weeks.
Serious adverse reactions were reported in 48% of patients. The most frequent serious adverse reactions reported were pneumonia (4.7%), upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general physical health deterioration (3.5%) and hypercalcemia (3.5%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 3.5% of patients who died of general physical health deterioration, multi-organ failure secondary to pulmonary aspergillosis, and disease progression.
Discontinuation of Kyprolis occurred in 19% of patients. The most frequent adverse reaction leading to discontinuation was asthenia (2%). Interruption of Kyprolis due to adverse reactions occurred in 77% of patients. Dose reduction of Kyprolis due to adverse reactions occurred in 31% of patients in DKd.
Infusion-related reactions that occurred following the first Kyprolis dose was 11%. Pulmonary hypertension adverse reactions were reported in 4.7% of patients in EQUULEUS.
Table 27 summarizes the adverse reactions in EQUULEUS. (See Table 27.)

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Adverse Reactions Occurring at a Frequency of < 15%: Blood and lymphatic system disorders: febrile neutropenia, thrombotic microangiopathy.
Cardiac disorders: cardiac failure, myocardial ischemia.
Gastrointestinal disorders: abdominal pain.
General disorders and administration site conditions: multiple organ dysfunction syndrome.
Infections: pneumonia, sepsis, septic shock.
Metabolism and nutrition disorders: dehydration, hypercalcemia.
Renal and urinary disorders: acute kidney injury, renal failure, renal impairment.
Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary hypertension.
Vascular disorders: hypotension.
Postmarketing Experience: The following adverse reactions have been identified during post approval use of 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), hepatitis B virus reactivation, gastrointestinal perforation, pericarditis, and cytomegalovirus infection including chorioretinitis, pneumonitis, enterocolitis, and viremia.

Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs [see Pharmacology: Pharmacokinetics under Actions].

Unopened vials should be stored refrigerated 2°C to 8°C. Retain in original package to protect from light.

Discuss the following with patients prior to treatment with Kyprolis: Cardiac Toxicities: Advise patients of the risks and symptoms of cardiac failure and ischemia [see Cardiac Toxicities under Precautions].
Dehydration: Counsel patients to avoid dehydration, since patients receiving Kyprolis therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dehydration [see Tumor Lysis Syndrome under Precautions].
Respiratory: Advise patients that they may experience cough or shortness of breath (dyspnea) during treatment with Kyprolis. This most commonly occurs within a day of dosing. Advise patients to contact their healthcare provider if they experience shortness of breath [see Dyspnea under Precautions].
Venous Thrombosis: Inform patients of the risk of venous thromboembolism and discuss the options for prophylaxis. Advise patients to seek immediate medical attention for symptoms of venous thrombosis or embolism [see Venous Thrombosis under Precautions].
Infusion-Related Reactions: Advise patients of the risk of infusion-related reactions, and discuss the common signs and symptoms of infusion-related reactions with the patients [see Infusion-Related Reactions under Precautions].
Bleeding: Inform patients that they may bruise or bleed more easily or that it may take longer to stop bleeding, and to report to their healthcare provider any prolonged, unusual or excessive bleeding. Instruct patients on the signs of occult bleeding [see Hemorrhage under Precautions].
Hepatic: Inform patients of the risk of developing hepatic failure. Advise patients to contact their healthcare provider for symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Hepatic Toxicity and Hepatic Failure under Precautions].
Other: Inform patients to contact their healthcare provider if they experience neurologic symptoms such as headaches, confusion, dizziness or loss of balance, difficulty talking or walking, decreased strength or weakness on one side of the body, seizures, or visual loss [see Precautions and Adverse Reactions].
Driving/Operating Machines: Advise patients that Kyprolis may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms [see Clinical Trials Experience under Adverse Reactions].
Embryo-Fetal Toxicity: Advise females of the potential risk to the fetus. Advise females of reproductive potential to inform their healthcare provider immediately of a known or suspected pregnancy. Advise female patients to use effective contraceptive during treatment with Kyprolis and for 6 months following the final dose. Advise male patients with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the final dose [see Embryo-Fetal Toxicity under Precautions, Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
Lactation: Advise patients to avoid breastfeeding while receiving Kyprolis and for 2 weeks after the final dose [see Lactation under Use in Pregnancy & Lactation].
Concomitant Medications: Advise patients to discuss with their healthcare provider any medication they are currently taking prior to starting treatment with Kyprolis, or prior to starting any new medication(s) during treatment with Kyprolis.

Targeted Cancer Therapy

L01XG02 - carfilzomib ; Belongs to the class of proteasome inhibitors. Used in the treatment of cancer.

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