Carfilzomib

Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor. In preclinical models of haematological tumours it has antiproliferative and pro-apoptotic activity, and in animals it delayed the growth of multiple myeloma tumours.

Mechanism of Action

• Irreversible proteasome binding: carfilzomib binds selectively and irreversibly to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core of the 26S proteasome. It has little to no activity against other classes of protease.
• Key catalytic site: the 20S core has chymotrypsin-like, trypsin-like and caspase-like sites. Inhibiting the chymotrypsin-like site (β5 and β5i subunits) is the most effective way to reduce cell proliferation and leads to cell-cycle arrest and apoptosis; at higher doses carfilzomib also inhibits the other two sites.
• Degree of inhibition: doses of 15 mg/m² or more consistently inhibited at least 80% of chymotrypsin-like proteasome activity in blood 1 hour after the first dose. The immunoproteasome subunits LMP2 and MECL1 were inhibited by 26–32% and 41–49% at 20 mg/m². Inhibition lasted at least 48 hours after the first dose of each week of dosing.
• Higher dose: at 56 mg/m², chymotrypsin-like inhibition was at least 90%, with greater inhibition of other subunits (LMP7, MECL1 and LMP2, by about 8%, 23% and 34% more than at 15–20 mg/m²).
• Combination: lenalidomide and dexamethasone did not affect proteasome inhibition.
• Selectivity in vitro: minimal neurotoxicity and minimal reaction with non-proteasomal proteases.
• Resistance: resistance has been observed. The mechanism is unconfirmed, but up-regulation of P-glycoprotein may contribute.

Pharmacokinetics

• Exposure: after a 2- to 10-minute infusion of 27 mg/m², Cmax was 4,232 ng/mL and AUC 379 ng·h/mL. Exposure rises with dose between 20 and 56 mg/m². A 30-minute infusion gives a similar half-life and AUC but a 2- to 3-fold lower Cmax; at 56 mg/m² over 30 minutes, AUC was 948 ng·h/mL (about 2.5 times that at 27 mg/m²) and Cmax 2,079 ng/mL. There is no systemic accumulation with repeated dosing (15 and 20 mg/m², days 1 and 15 or 16 of cycle 1).
• Distribution: the mean steady-state volume of distribution is about 28 L at 20 mg/m². In vitro binding to human plasma proteins averages 97% (0.4–4 micromolar).
• Metabolism: rapid and extensive. The main metabolites in plasma and urine are peptide fragments and the diol of carfilzomib, so peptidase cleavage and epoxide hydrolysis are the principal pathways; cytochrome P450 plays a minor role. The metabolites have no known biological activity.
• Elimination: half-life of 1 hour or less on day 1 of cycle 1 (doses of 15 mg/m² or more). Systemic clearance is 151–263 L/hour, above hepatic blood flow, so clearance is largely extrahepatic. Carfilzomib is eliminated mainly by metabolism, with the metabolites excreted in urine.
• Special populations: age, sex and race have no effect on pharmacokinetics in population analyses. Paediatric data are too limited to draw conclusions.

Carfilzomib is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy, always in combination with:

• daratumumab and dexamethasone;
• lenalidomide and dexamethasone; or
• dexamethasone alone.

• Hypersensitivity to carfilzomib or to any of the excipients.
• Breastfeeding.
• Because carfilzomib is given in combination with other medicines, the contraindications in the summaries of product characteristics of daratumumab, lenalidomide and dexamethasone also apply.

The frequencies below come from pooled clinical studies (3,878 patients). The most common reactions, occurring in more than 20% of patients, were anaemia, fatigue, thrombocytopenia, nausea, diarrhoea, pyrexia, dyspnoea, respiratory tract infection, cough and neutropenia. Cardiac toxicity and dyspnoea typically occurred early in the course of treatment.

A cross-study comparison suggests that cardiac failure, dyspnoea, hypertension and pulmonary hypertension may be dose-related. They were reported more often with the 56 mg/m² regimen with dexamethasone (cardiac failure 8.2%, dyspnoea 30.9%, hypertension 25.9%, pulmonary hypertension 1.3%) than with the 27 mg/m² regimen with lenalidomide and dexamethasone (6.4%, 22.7%, 15.8% and 0.8%).

In the study comparing carfilzomib with daratumumab and dexamethasone against carfilzomib with dexamethasone, deaths from adverse events within 30 days of the last dose occurred in 10% versus 5% of patients, most often from infections (5% versus 3%); the risk of fatal events was higher in patients aged 65 or over. Serious adverse events occurred in 56% versus 46%, most commonly pneumonia (12% versus 9%), pyrexia (4% versus 2%), influenza (4% versus 1%), sepsis (4% versus 1%), anaemia (2% versus 1%), diarrhoea (2% versus 0%) and bronchitis (2% versus 0%).

Very common (≥1/10): pneumonia, respiratory tract infection, thrombocytopenia, neutropenia, anaemia, lymphopenia, leukopenia, hypokalaemia, hyperglycaemia, decreased appetite, insomnia, dizziness, peripheral neuropathy, headache, hypertension, dyspnoea, cough, vomiting, diarrhoea, constipation, abdominal pain, nausea, back pain, arthralgia, pain in an extremity, muscle spasms, raised blood creatinine, pyrexia, peripheral oedema, asthenia, fatigue, chills.

Common (≥1/100 to <1/10): sepsis, lung infection, influenza, herpes zoster, urinary tract infection, bronchitis, gastroenteritis, viral infection, nasopharyngitis, rhinitis, febrile neutropenia, dehydration, hyperkalaemia, hypomagnesaemia, hyponatraemia, hypercalcaemia, hypocalcaemia, hypophosphataemia, hyperuricaemia, hypoalbuminaemia, anxiety, confusional state, paraesthesia, hypoaesthesia, cataract, blurred vision, tinnitus, cardiac failure, myocardial infarction, atrial fibrillation, tachycardia, decreased ejection fraction, palpitations, deep vein thrombosis, hypotension, flushing, pulmonary embolism, pulmonary oedema, epistaxis, oropharyngeal pain, dysphonia, wheezing, pulmonary hypertension, gastrointestinal haemorrhage, dyspepsia, toothache, raised ALT, AST and gamma-glutamyltransferase, hyperbilirubinaemia, rash, pruritus, erythema, hyperhidrosis, musculoskeletal pain, musculoskeletal chest pain, bone pain, myalgia, muscular weakness, acute kidney injury, renal failure, renal impairment, decreased renal creatinine clearance, chest pain, pain, infusion site reactions, influenza-like illness, malaise, raised C-reactive protein, raised blood uric acid.

Uncommon (≥1/1,000 to <1/100): Clostridium difficile colitis, cytomegalovirus infection, hepatitis B virus reactivation, drug hypersensitivity, haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, tumour lysis syndrome, intracranial haemorrhage, stroke, posterior reversible encephalopathy syndrome, cardiac arrest, myocardial ischaemia, pericarditis, pericardial effusion, ventricular tachycardia, hypertensive crisis, haemorrhage, acute respiratory distress syndrome, acute respiratory failure, pulmonary haemorrhage, interstitial lung disease, pneumonitis, gastrointestinal perforation, acute pancreatitis, hepatic failure, cholestasis, multi-organ dysfunction syndrome.

Rare (≥1/10,000 to <1/1,000): thrombotic microangiopathy, hypertensive emergency, angioedema.

Serious reactions listed in the SmPC include cardiac failure, myocardial infarction, cardiac arrest, myocardial ischaemia, interstitial lung disease, pneumonitis, acute respiratory distress syndrome, acute respiratory failure, pulmonary hypertension, hypertensive crises, acute kidney injury, tumour lysis syndrome, infusion-related reactions, gastrointestinal, intracranial and pulmonary haemorrhage, thrombocytopenia, hepatic failure, hepatitis B virus reactivation, posterior reversible encephalopathy syndrome (PRES), thrombotic microangiopathy and thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome (TTP/HUS).

Carfilzomib is broken down mainly by peptidase and epoxide hydrolase activity, so its levels are unlikely to be changed by inhibitors or inducers of cytochrome P450 enzymes.

• CYP3A4/5: in a clinical study with oral midazolam as a probe (carfilzomib 27 mg/m²), the probe’s pharmacokinetics were unaffected. Carfilzomib is therefore not expected to inhibit CYP3A4/5 substrates or to induce CYP3A4. No study was done at 56 mg/m².
• Other CYP enzymes: carfilzomib did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19 or 2D6 in vitro. It is not known whether it induces CYP1A2, 2C8, 2C9, 2C19 and 2B6 at therapeutic concentrations, so caution is advised with medicines that are substrates of these enzymes.
• Oral contraceptives: they are substrates of these enzymes, so their effectiveness may be reduced. Patients using them should switch to an alternative method of effective contraception. Hormonal contraceptives that carry a thrombosis risk should in any case be avoided, because carfilzomib increases the risk of venous thromboembolism.
• P-glycoprotein (P-gp): carfilzomib is a P-gp substrate but not a BCRP substrate. Because it is given intravenously and extensively metabolised, inhibitors or inducers of P-gp or BCRP are unlikely to change its levels. In vitro, at concentrations lower than those expected at therapeutic doses, it inhibited the efflux transport of digoxin, a P-gp substrate, by 25%, so caution is appropriate with digoxin and other P-gp substrates.
• Medicines given together with carfilzomib: the interactions in the summaries of product characteristics of daratumumab, lenalidomide and dexamethasone also apply.

Treatment should be supervised by a physician experienced in anti-cancer therapy. Carfilzomib is given only as an intravenous infusion. The dose is calculated from the patient’s baseline body surface area (BSA); for a BSA above 2.2 m², the dose is based on 2.2 m². The dose does not need to change for weight changes of 20% or less. Each treatment cycle lasts 28 days: carfilzomib is given on days 1, 2, 8, 9, 15 and 16, followed by a 12-day rest period (days 17 to 28).

With Lenalidomide and Dexamethasone

• Infusion time: 10 minutes throughout.
• Cycle 1: 20 mg/m² on days 1 and 2 (maximum 44 mg). If tolerated, 27 mg/m² (maximum 60 mg) on days 8, 9, 15 and 16.
• Cycles 2–12: 27 mg/m² on days 1, 2, 8, 9, 15 and 16.
• From cycle 13: the day 8 and 9 doses are omitted (27 mg/m² on days 1, 2, 15 and 16).
• Duration: until disease progression or unacceptable toxicity. Treatment beyond 18 cycles should rest on an individual benefit/risk assessment, because data on tolerability and toxicity beyond 18 cycles are limited.
• Partner medicines: lenalidomide 25 mg by mouth on days 1–21; dexamethasone 40 mg by mouth or intravenously on days 1, 8, 15 and 22. The starting dose of lenalidomide should be reduced where its own SmPC advises, for example in baseline renal impairment.

With Dexamethasone Alone

• Infusion time: 30 minutes throughout.
• Cycle 1: 20 mg/m² on days 1 and 2 (maximum 44 mg). If tolerated, 56 mg/m² (maximum 123 mg) on days 8, 9, 15 and 16.
• Cycle 2 and later: 56 mg/m² on days 1, 2, 8, 9, 15 and 16.
• Duration: until disease progression or unacceptable toxicity.
• Dexamethasone: 20 mg by mouth or intravenously on days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day cycle.

With Daratumumab and Dexamethasone

• Carfilzomib: the same schedule as with dexamethasone alone (30-minute infusion; 20 mg/m² on days 1 and 2 of cycle 1, then 56 mg/m²; maximum 44 mg and 123 mg), until disease progression or unacceptable toxicity.
• Dexamethasone: 20 mg by mouth or intravenously on days 1, 2, 8, 9, 15 and 16, and 40 mg on day 22 of each 28-day cycle. For patients over 75 years, 20 mg weekly after the first week.
• Daratumumab, intravenous: 16 mg/kg actual body weight, given as 8 mg/kg on days 1 and 2 of cycle 1; then 16 mg/kg weekly on days 8, 15 and 22 of cycle 1 and days 1, 8, 15 and 22 of cycle 2; then every 2 weeks for 4 cycles (cycles 3 to 6); then every 4 weeks until progression.
• Daratumumab, subcutaneous: 1,800 mg on days 1, 8, 15 and 22 of cycles 1 and 2; then every 2 weeks for 4 cycles (cycles 3 to 6); then every 4 weeks until progression.
• Sequence on days when several are given: dexamethasone, daratumumab pre-infusion medicines, carfilzomib, daratumumab, daratumumab post-infusion medicines.

Premedication and Supportive Measures

• Dexamethasone is given 30 minutes to 4 hours before carfilzomib.
• Antiviral prophylaxis should be considered to reduce the risk of herpes zoster reactivation.
• Thromboprophylaxis is recommended with all three combinations, based on the patient’s underlying risks and clinical status.
• Hydration is required before dosing in cycle 1, especially in patients at high risk of tumour lysis syndrome or kidney toxicity: oral fluids of 30 mL/kg/day for 48 hours before day 1 of cycle 1, and 250 to 500 mL of intravenous fluid before each cycle 1 dose, with a further 250 to 500 mL afterwards if needed. Hydration continues in later cycles as needed. It is not required on days when intravenous daratumumab is given. The total fluid volume may be adjusted in patients with, or at risk of, cardiac failure.
• Serum potassium is monitored monthly, or more often as clinically indicated.

Dose Adjustments for Side Effects

• Neutrophils below 0.5 × 10⁹/L: stop the dose. If they recover to 0.5 × 10⁹/L or more, continue at the same dose level. For later drops, repeat this and consider one dose level lower when restarting.
• Febrile neutropenia (neutrophils below 0.5 × 10⁹/L with an oral temperature above 38.5 °C, or two readings above 38.0 °C for 2 hours): stop the dose; resume at the same dose level once neutrophils return to baseline grade and the fever has gone.
• Platelets below 10 × 10⁹/L, or bleeding with thrombocytopenia: stop the dose. If platelets recover to 10 × 10⁹/L or more and/or the bleeding is controlled, continue at the same dose level. For later drops, repeat this and consider one dose level lower.
• Kidney toxicity (serum creatinine at least twice baseline; creatinine clearance below 15 mL/min or down to 50% of baseline or less; or need for dialysis): stop the dose and keep monitoring. Restart when renal function is within 25% of baseline, considering one dose level lower. In patients on dialysis, give the dose after dialysis.
• Other grade 3 or 4 non-haematological toxicity: stop until resolved or back to baseline, and consider restarting the next scheduled dose one level lower.
• Dose levels: with lenalidomide and dexamethasone, 27 mg/m² then 20 mg/m² then 15 mg/m². With dexamethasone alone, or with daratumumab and dexamethasone, 56 mg/m² then 45 mg/m² then 36 mg/m² then 27 mg/m². Infusion times stay the same. If symptoms do not resolve at the last level, carfilzomib is discontinued.

Special Populations

• Renal impairment: no change to the starting dose for mild, moderate or severe impairment or for chronic dialysis, based on pharmacokinetic data. Acute renal failure was more frequent in patients with lower baseline creatinine clearance, so renal function is assessed at the start and monitored at least monthly, particularly below 30 mL/min, where data are limited. Data for the combination with lenalidomide and dexamethasone are limited below 50 mL/min. Dialysis clearance has not been studied, so the dose is given after dialysis.
• Hepatic impairment: no change to the starting dose for mild or moderate impairment; pharmacokinetics have not been evaluated in severe impairment. Liver abnormalities, grade 3 or higher events and serious events were more frequent in mild or moderate impairment, so liver enzymes and bilirubin are checked at the start and monthly. Data in moderate and severe impairment are very limited.
• Elderly: certain adverse events, including cardiac failure, were more frequent in patients aged 75 or over.
• Children and adolescents: there is no relevant use in multiple myeloma below 18 years.

Method of Administration

Carfilzomib must not be given as an intravenous push or bolus. The 20/27 mg/m² dose is infused over 10 minutes and the 20/56 mg/m² dose over 30 minutes. The intravenous line is flushed with sodium chloride 0.9% or glucose 5% solution immediately before and after the infusion. Carfilzomib must not be mixed or infused with other medicinal products. The powder is reconstituted before use according to the instructions in the SmPC.

Use With Other Medicines

Because carfilzomib is given in combination, the summaries of product characteristics of the other medicines must be read before treatment starts. When lenalidomide is used, its pregnancy testing and prevention requirements need particular attention.

Heart Problems

New or worsening cardiac failure (including congestive cardiac failure, pulmonary oedema and decreased ejection fraction), myocardial ischaemia and infarction have occurred. Death from cardiac arrest has occurred within a day of a dose, and fatal outcomes have been reported with cardiac failure and myocardial infarction.

• Patients are monitored for volume overload, especially if at risk of cardiac failure.
• Carfilzomib is stopped for grade 3 or 4 cardiac events until recovery; a restart one dose level lower is considered on a benefit/risk basis.
• The risk of cardiac failure is higher in patients aged 75 or over and in Asian patients. Cardiovascular risk factors should be assessed before treatment.
• Patients with NYHA class III or IV heart failure, a myocardial infarction in the last 4 months, or uncontrolled angina or arrhythmias were not in the studies. They need a comprehensive cardiological assessment first and close follow-up afterwards.
• QT interval prolongation and ventricular tachycardia have been reported.

Lung Problems

Acute respiratory distress syndrome, acute respiratory failure and acute diffuse infiltrative lung disease such as pneumonitis and interstitial lung disease have occurred, some fatal. Pulmonary hypertension has also been reported, some fatal. Carfilzomib is stopped until these resolve (or return to baseline), and a restart is a benefit/risk decision. Dyspnoea is common: it should be evaluated to exclude heart and lung conditions, and carfilzomib is stopped for grade 3 and 4 dyspnoea until resolved or back to baseline.

Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed, some of it fatal, and was reported more often when carfilzomib was combined with daratumumab. Blood pressure should be controlled before and during treatment and checked routinely. The dose is reduced if hypertension cannot be controlled, and carfilzomib is stopped in a hypertensive crisis until it resolves.

Kidney Problems

Acute renal failure has been reported, some fatal. Renal function is monitored at least monthly, or according to accepted clinical guidelines, particularly in patients with lower baseline creatinine clearance, and the dose is reduced or stopped as appropriate.

Tumour Lysis Syndrome

Cases, including fatal ones, have been reported; patients with a high tumour burden are at greater risk. Patients should be well hydrated before cycle 1 and, as needed, in later cycles. Uric acid-lowering medicines should be considered in high-risk patients. Serum electrolytes are measured regularly, and carfilzomib is stopped until the syndrome resolves.

Infusion Reactions

Infusion reactions, including life-threatening ones, have been reported. Symptoms may include fever, chills, joint or muscle pain, facial flushing or swelling, vomiting, weakness, shortness of breath, low blood pressure, fainting, slow heart rate, chest tightness or angina. They can occur immediately or up to 24 hours after a dose. Dexamethasone before each dose reduces how often and how severe they are.

Bleeding and Low Platelets

Haemorrhage (gastrointestinal, pulmonary and intracranial), often with thrombocytopenia, has been reported and some cases were fatal. Platelet counts are lowest on day 8 or day 15 of each 28-day cycle and recover by the start of the next. Platelets are monitored frequently, and the dose reduced or stopped as appropriate.

Venous Thromboembolism

Deep vein thrombosis and pulmonary embolism, some fatal, have been reported. Patients with risk factors, including earlier thrombosis, need close monitoring, and modifiable risk factors (smoking, hypertension, hyperlipidaemia) should be minimised. Caution is needed with other agents that may raise thrombosis risk, such as erythropoietic agents or hormone replacement therapy. Patients should seek medical care for shortness of breath, chest pain, coughing up blood, or arm or leg swelling or pain.

Liver Problems

Hepatic failure, including fatal cases, and raised transaminases have been reported. Liver enzymes and bilirubin are checked at the start and monthly during treatment, whatever the baseline values, and the dose is reduced or stopped as appropriate.

Thrombotic Microangiopathy

Thrombotic microangiopathy, including TTP/HUS, has been reported, some cases fatal. Patients are monitored for signs. If it is suspected, carfilzomib is stopped and the patient evaluated; if the diagnosis is excluded, carfilzomib can be restarted. The safety of restarting after TTP/HUS is not known.

Posterior Reversible Encephalopathy Syndrome

PRES is a rare neurological disorder that can present with seizure, headache, lethargy, confusion, blindness, altered consciousness and other visual and neurological disturbances, together with hypertension; neuro-radiological imaging confirms it. Carfilzomib is discontinued if PRES is suspected. The safety of restarting is not known.

Hepatitis B Virus Reactivation

All patients should be screened for hepatitis B virus before treatment. For positive serology, antiviral prophylaxis should be considered, with monitoring for clinical and laboratory signs of reactivation during and after treatment and advice from specialists as needed. Resuming carfilzomib after reactivation is controlled should be discussed with experts in managing hepatitis B.

Progressive Multifocal Leukoencephalopathy

Cases have been reported in patients with earlier or concurrent immunosuppressive therapy. Patients are monitored for new or worsening neurological, cognitive or behavioural signs. If it is suspected, treatment is suspended until a specialist has excluded it, and carfilzomib is discontinued if it is confirmed.

Pregnancy, Breastfeeding and Contraception

• Women of childbearing potential: effective contraception during treatment and for one month afterwards (the patient and/or partner). Carfilzomib may reduce the efficacy of oral contraceptives. Because of the higher risk of venous thromboembolism, hormonal contraceptives that carry a thrombosis risk should be avoided, and a patient using one should switch to another effective method.
• Men: effective contraception during treatment and for 3 months afterwards if the partner is pregnant or of childbearing potential and not using effective contraception.
• Pregnancy: there are no data in pregnant women, and animal studies showed reproductive toxicity. Based on its mechanism and animal findings, carfilzomib can cause foetal harm, so it should not be used in pregnancy unless the potential benefit outweighs the risk to the foetus. If it is used, or the patient becomes pregnant, she should be told of the potential hazard. Lenalidomide is structurally related to thalidomide, a known human teratogen that causes severe life-threatening birth defects.
• Breastfeeding: contraindicated.

Excipients With Known Effect

• Sodium: 37 mg per 10 mg vial, 109 mg per 30 mg vial and 216 mg per 60 mg vial, equal to 1.9%, 5.5% and 11% of the WHO recommended maximum daily sodium intake of 2 g for an adult.
• Cyclodextrin (betadex sulfobutyl ether sodium): 500 mg, 1,500 mg and 3,000 mg per 10 mg, 30 mg and 60 mg vial, equal to 88 mg/kg for a 70 kg adult.

Effect on Driving

Carfilzomib has a minor influence on the ability to drive and use machines. Fatigue, dizziness, fainting, blurred vision, drowsiness and/or a drop in blood pressure have been observed. Patients who have any of these should not drive or operate machines.

Store the vials in a refrigerator at 2–8 °C, in the original carton to protect from light. Do not freeze. Vials are shipped and held under cold-chain conditions until the hospital pharmacy prepares them.

After reconstitution, the solution is stable in the vial, syringe or intravenous bag for 24 hours at 2–8 °C or for 4 hours at 25 °C.

3 years for the unopened vial. The reconstituted solution should preferably be used immediately; the time from reconstitution to administration must not exceed 24 hours. If it is not used immediately, in-use storage times and conditions are the responsibility of the user and should not be longer than 24 hours at 2–8 °C.

Prescription only (Rx). Treatment must be supervised by a physician experienced in anti-cancer therapy. Carfilzomib is given by intravenous infusion in hospital, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.