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:

o      Lenalidomide and dexamethasone; or

o      Dexamethasone; or

o      Daratumumab and dexamethasone; or

o      Daratumumab and hyaluronidase-fihj and dexamethasone.

·             Kyprolis is indicated as a single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

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 section 4.4).

Electrolyte Monitoring

Monitor serum potassium levels regularly during treatment with Kyprolis (see section 4.8).

Premedications and Concomitant Medications

Premedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the combination therapy (see section 4.2). 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-related reactions (see section 4.4). Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.

Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies (see section 4.4).

Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation (see section 4.8).

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.

Posology

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 1 (see section 5.1). 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.

Table 1: Kyprolis 20/27 mg/m² twice weekly (10‑minute infusion) in combination with lenalidomide and dexamethasone

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 2 (see section 5.1). 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.

Table 2: Kyprolis 20/70 mg/m² once weekly (30‑minute infusion) in combination with dexamethasone

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 3 (see section 5.1). 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.

Table 3: Kyprolis 20/56 mg/m² twice weekly (30‑minute infusion) in combination with dexamethasone

Kyprolis in Combination with Daratumumab and Dexamethasone or Daratumumab and Hyaluronidase-fihj 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 the daratumumab and dexamethasone or daratumumab and hyaluronidase-fihj and dexamethasone until disease progression or unacceptable toxicity as shown in Table 4 (see section 5.1). 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 daratumumab or daratumumab and hyaluronidase-fihj. Refer to the Prescribing Information for daratumumab, daratumumab and hyaluronidase-fihj and dexamethasone for additional dosage information.

Table 4: Kyprolis 20/56 mg/m² twice weekly (30‑minute infusion) in combination with daratumumab or daratumumab and hyaluronidase-fihj and dexamethasone

*For patients > 75 years of age, administer 20 mg of dexamethasone orally or intravenously weekly after the first week.

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 daratumumab and dexamethasone or daratumumab and hyaluronidase-fihj and dexamethasone until disease progression or unacceptable toxicity as shown in Table 5 (see section 5.1). 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 daratumumab or daratumumab and hyaluronidase-fihj. Refer to the Prescribing Information for daratumumab, daratumumab and hyaluronidase-fihj, and dexamethasone for additional dosage information.

Table 5: Kyprolis 20/70 mg/m² once weekly (30‑minute infusion) in combination with daratumumab or daratumumab and hyaluronidase-fihj and dexamethasone

*For patients > 75 years of age, administer 20 mg of dexamethasone orally or intravenously weekly after the first week.

Kyprolis monotherapy

20/27 mg/m² twice weekly regimen by 10‑minute infusion

Administer Kyprolis intravenously as a 10‑minute infusion (see section 5.1). In Cycles 1 through 12, administer Kyprolis on Days 1, 2, 8, 9, 15 and 16 of each 28‑day cycle as shown in Table 6. From Cycle 13, administer Kyprolis on Days 1, 2, 15 and 16 of each 28-day cycle. Premedicate with dexamethasone 4 mg orally or intravenously 30 minutes to 4 hours before each Kyprolis dose in Cycle 1, then as needed to minimize infusion-related reactions (see section 4.2). 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 and thereafter. Continue Kyprolis until disease progression or unacceptable toxicity.

Table 6: Kyprolis monotherapy 20/27 mg/m² twice weekly (10-minute infusion)

20/56 mg/m² twice weekly regimen by 30‑minute infusion

Administer Kyprolis intravenously as a 30‑minute infusion (see section 5.1). In Cycles 1 through 12, administer Kyprolis on Days 1, 2, 8, 9, 15 and 16 of each 28‑day cycle as shown in Table 7. From Cycle 13, administer Kyprolis on Days 1, 2, 15 and 16 of each 28-day cycle. Premedicate with dexamethasone 8 mg orally or intravenously 30 minutes to 4 hours before each Kyprolis dose in Cycle 1, then as needed to minimize infusion-related reactions (see section 4.2). 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. Continue Kyprolis until disease progression or unacceptable toxicity.

Table 7: Kyprolis monotherapy 20/56 mg/m² twice weekly (30‑minute infusion)

Dosage modifications for adverse reactions

Recommended actions and dosage modifications for Kyprolis are presented in Table 8. Dose level reductions are presented in Table 9. See the lenalidomide, intravenous daratumumab, and dexamethasone Prescribing Information respectively for recommended dosage modifications associated with each product.

Table 8: Dosage modifications for adverse reactions^a

Table 9: Dose level reductions for adverse reactions

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 sections 4.8 and 5.2).

Recommended dosage for end stage renal disease (ESRD)

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

Method of administration

Kyprolis should be administered over 10 or 30 minutes depending on the Kyprolis dose regimen. Do not administer as an intravenous push or bolus. Flush the intravenous administration line with normal saline or 5% dextrose injection, immediately before and after Kyprolis administration. Do not mix Kyprolis with or administer as an infusion with other medicinal products.

For instructions on the handling and preparation of the medicinal product before administration (see section 6.6).

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 section 4.8).

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 section 4.2).

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 section 4.2).

In patients ≥ 75 years of age, the risk of cardiac failure is increased compared to younger 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 section 4.8).

Electrocardiographic changes

There have been cases of QT interval prolongation reported in clinical studies. An effect of Kyprolis on QT interval cannot be excluded.

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. 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 section 4.2).

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.

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 section 4.2).

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 sections 4.4 and 4.8).

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. With Kyprolis monotherapy, the incidence of venous thromboembolic events was 2%.

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 section 4.6).

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, bradycardia, 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 sections 4.2 and 4.8).

Hemorrhage

Fatal or serious cases of hemorrhage have been reported in patients treated with Kyprolis (see section 4.8). 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 section 4.2).

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 section 4.8). Thrombocytopenia was reported in approximately 32% of patients in clinical trials with Kyprolis. Hemorrhage may occur (see sections 4.4 and 4.8).

Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate (see section 4.2).

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 section 4.8).

Monitor liver enzymes regularly, regardless of baseline values. Reduce or withhold dose as appropriate (see section 4.2).

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 contributory 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 last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the last dose.

Sodium content

This medicinal product contains 216 mg sodium per 60 mg vial which is equivalent to 11% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Cyclodextrin content

This medicinal product contains 3000 mg sodium sulfobutylether beta-cyclodextrin per 60 mg vial which is equivalent to 88 mg/kg for a 70 kg adult.

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.

In vitro studies indicated that carfilzomib did not induce human CYP3A4 in cultured human hepatocytes. A clinical trial using oral midazolam as a CYP3A probe conducted with carfilzomib at a dose of 27 mg/m² (2‑10 minute infusion) demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant carfilzomib administration, indicating that carfilzomib is not expected to inhibit the metabolism of CYP3A4/5 substrates and is not a CYP3A4 inducer in human subjects. No clinical trial was conducted with a dose of 56 mg/m². However, it is unknown whether carfilzomib is an inducer of CYP1A2, 2C8, 2C9, 2C19 and 2B6 at therapeutic concentrations. Caution should be observed when carfilzomib is combined with medicinal products that are substrates of these enzymes, such as oral contraceptives. Effective measures to avoid pregnancy should be taken (see section 4.4, and refer also to the current lenalidomide summary of product characteristics), an alternative method of effective contraception should be used if the patient is using oral contraceptives.

Carfilzomib does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19 and 2D6 in vitro and is therefore not expected to influence exposure of medicinal products that are substrates of these enzymes as a result of inhibition.

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.

Pregnancy

Kyprolis can cause fetal harm based on findings from animal studies and its mechanism of action (see section 5.1). 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 section 5.3). 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.

Lactation

It is unknown whether carfilzomib or its metabolites are excreted in human milk. Based on its pharmacological properties, a risk to the suckling child cannot be excluded. Consequently, as a precautionary measure, breast‑feeding is contra‑indicated during and for at least 2 days after treatment with Kyprolis.

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 6 months following the last dose.

Males

Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the last dose.

Infertility

Based on the mechanism of action, Kyprolis may have an effect on either male or female fertility (see sections 5.1 and 5.3). There are no data on the effect of Kyprolis on human fertility.

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 section 4.8).

The following clinically significant adverse reactions are discussed in greater detail in section 4.4:

·        Cardiac toxicities

·        Acute renal failure

·        Tumor lysis syndrome

·        Pulmonary toxicity

·        Pulmonary hypertension

·        Dyspnea

·        Hypertension

·        Venous thrombosis

·        Infusion-related reactions

·        Hemorrhage

·        Thrombocytopenia

·        Hepatic toxicity and hepatic failure

·        Thrombotic microangiopathy

·        Posterior reversible encephalopathy syndrome

·        Progressive multifocal leukoencephalopathy

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 practice.

The pooled safety population described in the section 4.4 Special warnings and precautions for use 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 occurring 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 (see section 5.1). 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 reactions within 30 days of the last dose of 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 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.

Table 10 summarizes the adverse reactions in the first 12 cycles in ASPIRE.

Table 10: Adverse reactions (≥ 10%) occurring in Cycles 1–12 in patients who received KRd (20/27 mg/m² regimen) in ASPIRE

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, ventricular tachycardia

·        Ear and labyrinth disorders: deafness, tinnitus

·        Eye disorders: cataract, vision blurred

·        Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache, acute pancreatitis

·        General disorders and administration site conditions: chills, infusion site reaction, multi‑organ failure, pain

·        Infections: clostridium difficile colitis, influenza, lung infection, rhinitis, sepsis, urinary tract infection, viral infection (Herpes Zoster, Cytomegalovirus 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, confusional state

·        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, angioedema

·        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 11 describes Grade 3–4 laboratory abnormalities reported in ASPIRE.

Table 11: Grade 3–4 laboratory abnormalities (≥ 10%) in Cycles 1–12 in patients who received KRd (20/27 mg/m² regimen) in ASPIRE

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 (see section 5.1). Patients received treatment for a median duration of 48 weeks in the Kd 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 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 12.

Table 12: Adverse reactions (≥ 10%) occurring in months 1–6 in patients who received Kd (20/56 mg/m² regimen) in ENDEAVOR

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, ventricular tachycardia

·        Ear and labyrinth disorders: tinnitus

·        Eye disorders: cataract, vision blurred

·        Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache, acute pancreatitis

·        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: bronchopneumonia, gastroenteritis, influenza, lung infection, nasopharyngitis, pneumonia, rhinitis, sepsis, urinary tract infection, viral infection (Herpes Zoster, Cytomegalovirus 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, confusional state

·        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, angioedema

·        Vascular disorders: deep vein thrombosis, flushing, hypotension

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

Table 13: Grade 3–4 laboratory abnormalities (≥ 10%) in months 1–6 in patients who received Kd (20/56 mg/m² regimen) in ENDEAVOR

A.R.R.O.W.

The safety of Kyprolis in combination with dexamethasone was evaluated in A.R.R.O.W. (see section 5.1). 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 are presented in Table 14.

Table 14: Adverse reactions in patients who received Kd (≥ 10% in either Kd arm) in A.R.R.O.W.

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, ventricular tachycardia

·        Ear and labyrinth disorders: tinnitus

·        Eye disorders: cataract, vision blurred

·        Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, toothache, vomiting, acute pancreatitis

·        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: clostridium difficile colitis, gastroenteritis, influenza, lung infection, nasopharyngitis, rhinitis, sepsis, septic shock, urinary tract infection, viral infection (Herpes Zoster, Cytomegalovirus 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, confusional state

·        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, angioedema

·        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 section 5.1). 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 15 summarizes the adverse reactions in CANDOR.

Table 15: Adverse Reactions (≥ 15%) in patients who received either DKd or Kd (20/56 mg/m² regimen) in CANDOR

DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone

^a The incidence of infusion-related reactions is based on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd or Kd administration. 

^b Fatigue includes fatigue and asthenia. 

^c Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection.

^d Thrombocytopenia includes platelet count decreased and thrombocytopenia.

^e Anemia includes anemia, hematocrit decreased and hemoglobin decreased.

^f Cough includes productive cough and cough.

^g Includes fatal adverse reactions.

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, ventricular tachycardia

·             Eye disorders: cataract

·             Gastrointestinal disorders: abdominal pain, gastrointestinal hemorrhage, acute pancreatitis

·             General disorders and administration site conditions: chest pain, malaise

·             Infections: gastroenteritis, influenza, lung infection, nasopharyngitis, sepsis, septic shock, urinary tract infection, viral infection (Herpes Zoster, Cytomegalovirus 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, confusional state

·             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, angioedema

·             Vascular disorders: deep vein thrombosis, hypertensive crisis

EQUULEUS

The safety of Kyprolis 20/70 mg/m² once weekly in combination with intravenous daratumumab and dexamethasone (DKd) was evaluated in EQUULEUS (see section 5.1). 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 16 summarizes the adverse reactions in EQUULEUS.

Table 16: Adverse reactions (≥ 15%) in patients who received DKd (20/70 mg/m² regimen) in EQUULEUS

DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone

^a Thrombocytopenia includes platelet count decreased and thrombocytopenia.

^b Anemia includes anemia, hematocrit decreased and hemoglobin decreased.

^c Neutropenia includes neutrophil count decreased and neutropenia.

^d Lymphopenia includes lymphocyte count decreased and lymphopenia.

^e Fatigue includes fatigue and asthenia. 

^f The incidence of infusion-related reactions is based on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd administration.

^g Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection.

^h Cough includes productive cough and cough.

Adverse reactions occurring at a frequency of < 15%

·             Blood and lymphatic system disorders: febrile neutropenia, thrombotic microangiopathy

·             Cardiac disorders: cardiac failure, myocardial ischemia, ventricular tachycardia

·             Gastrointestinal disorders: abdominal pain, acute pancreatitis

·             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

Kyprolis in combination with subcutaneous daratumumab and dexamethasone

The safety of Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone was evaluated in PLEIADES (see section 5.1).

PLEIADES

The safety of Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone (DKd) was evaluated in a single-arm cohort of PLEIADES. Patients received Kyprolis as a 30-minute IV infusion once weekly for three weeks (Days 1, 8, and 15), followed by a 13-day rest period (Days 16 to 28) and continued until disease progression or unacceptable toxicity (N = 66) in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Among these patients, 77% were exposed for 6 months or longer and 27% were exposed for greater than one year.

Serious adverse reactions occurred in 27% of patients who received Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Fatal adverse reactions occurred in 3% of patients who received Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone.

Permanent discontinuation of Kyprolis due to an adverse reaction occurred in 6% of patients who received Kyprolis.

Dosage interruptions due to an adverse reaction occurred in 46% of patients who received Kyprolis.

The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea and edema peripheral.

Table 17 summarizes the adverse reactions in patients who received Kyprolis with subcutaneous daratumumab and dexamethasone (DKd) in PLEIADES.

Clinically relevant adverse reactions in <10% of patients who received Kyprolis with subcutaneous daratumumab and dexamethasone include:

·             Gastrointestinal disorders: abdominal pain, constipation, pancreatitis

·             Infection and infestations: pneumonia, influenza, urinary tract infection, herpes zoster, sepsis

·             Metabolism and nutrition disorders: hyperglycemia, decreased appetite, hypocalcemia

·             Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia

·             Nervous system disorders: paresthesia, dizziness, syncope

·                 General disorders and administration site conditions: injection site reaction, infusion reactions, chills

·             Skin and subcutaneous tissue disorders: rash, pruritus

·             Cardiac disorders: cardiac failure

·             Vascular disorders: hypotension

Table 18 summarizes the laboratory abnormalities in patients who received Kyprolis with subcutaneous daratumumab and dexamethasone in PLEIADES.

Kyprolis in patients who received monotherapy

The safety of Kyprolis 20/27 mg/m² as a 10‑minute infusion was evaluated in clinical trials consisting of 598 patients with relapsed and/or refractory myeloma (see section 5.1). 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).

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.

Serious adverse reactions were reported in 50% of patients in the pooled Kyprolis monotherapy studies (N = 598). The most frequent 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 FOCUS, 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 (see section 5.1). The patients received a median of 4 (range 1–10) prior regimens.

Adverse reactions occurring with Kyprolis monotherapy are presented in Table 19.

Table 19: Adverse reactions (≥ 20%) with Kyprolis monotherapy

^a Dyspnea includes dyspnea and dyspnea exertional.

^b Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency.

^c Cough includes cough and productive cough.

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, ventricular tachycardia

·        Ear and labyrinth disorders: tinnitus

·        Eye disorders: cataract, blurred vision

·        Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, gastrointestinal hemorrhage, toothache, acute pancreatitis

·        General disorders and administration site conditions: asthenia, infusion site reaction, multi‑organ failure, pain

·        Hepatobiliary disorders: hepatic failure

·        Infections: 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, confusional state

·        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, angioedema

·        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.

Table 20 describes Grade 3–4 laboratory abnormalities reported at a rate of > 10% for patients who received Kyprolis monotherapy.

Table 20: Grade 3–4 laboratory abnormalities (> 10%) with Kyprolis monotherapy

Pediatric use

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

Geriatric use

Of the 2387 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 section 4.8). No overall differences in effectiveness were observed between older and younger patients.

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 sections 4.2 and 5.2).

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 sections 4.4 and 5.2).

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, viremia, intestinal obstruction and acute pancreatitis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to their local representative.

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.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX45

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.

Pharmacodynamic effects

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.

Clinical efficacy and safety

In combination with lenalidomide and dexamethasone for relapsed or refractory multiple myeloma

ASPIRE

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 21). 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.

Table 21: Demographics and baseline characteristics in ASPIRE
 

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 22 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 22 and Figure 2).

Table 22: Efficacy outcomes in ASPIRE^a

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 = months; OS = overall survival; Rd = lenalidomide and dexamethasone arm

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

ENDEAVOR was a randomized, open‑label, multicenter 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 23.

Table 23: Demographics and baseline characteristics in ENDEAVOR

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 24 and Figure 3).

Figure 3: Kaplan‑Meier plot of progression‑free survival in ENDEAVOR

CI = confidence interval; HR = hazard ratio; Kd = Kyprolis and 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). Results are provided in Table 24 and Figure 4.

Table 24: Summary of key results in ENDEAVOR

(Intent‑to‑treat population)^a

Figure 4: Kaplan-Meier plot of overall survival in ENDEAVOR

CI = confidence interval; HR = hazard ratio; Kd = Kyprolis and 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.

A.R.R.O.W. was a randomized, open‑label, multicenter superiority trial of Kyprolis and 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 25.

Table 25: Demographics and baseline characteristics in A.R.R.O.W.