Carfilzomib (Kyprolis) arrests the cell cycle and causes apoptosis by inhibiting proteasomes that are responsible for protein homeostasis.

It is used to treat the following conditions:

• Refractory or relapsed multiple myeloma as monotherapy in patients who have received one or more first-line therapies
• Refractory or relapsed multiple myeloma in combination with dexamethasone or lenalidomide plus dexamethasone in patients who have received 1 - 3 prior therapies.
• It is also used Off-Label in adults with newly diagnosed Multiple myeloma and Waldenström macroglobulinemia

Carfilzomib (Kyprolis) dose in Adults

Before infusing Carfilzomib, note the following:

• Hydrate the patient for at least two days before the start of the treatment with a minimum of 30 ml/kg of oral fluids per day)
• Intravenous fluids are recommended before and after each dose. A minimum of 500 ml saline may be required.
• Before and after the infusion is over, it is recommended to flush the IV line with either saline or dextrose water.
• Prophylactic antiviral (Acyclovir) treatment is indicated for those patients who have a recent history of Herpes Zoster infection.
• Administer GI and DVT prophylaxis, especially to patients who are given a combination of dexamethasone or lenalidomide plus dexamethasone along with Carfilzomib.
• Premedicate with dexamethasone.

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Carfilzomib (Kyprolis) dose (as off-label) for newly diagnosed Multiple Myeloma:

It is indicated in older people who are more than 65 years of age and are ineligible for autologous transplant:

Induction phase:

• Cycle 1:
  • 20 mg/m² intravenous over 30 minutes on days 1 and 2, and
  • 36 mg/m² intravenous over 30 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle along with cyclophosphamide and dexamethasone.
• Cycles 2 - 9:
  • 36 mg/m² intravenous over 30 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle along with cyclophosphamide and dexamethasone
• Maintenance phase:
  • 36 mg/m² intravenous on days 1, 2, 15, and 16 of a 28-day treatment cycle as monotherapy until either the disease shows signs of progression or the patient is not tolerating it.

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Carfilzomib (Kyprolis) dose for refractory or relapsed Multiple myeloma:

• Cycle 1:
  • Day 1 and 2: 20 mg/m²
  • Days 8, 9, 15, and 16: 27 mg/m²
• Cycles 2 - 12:
  • Days 1, 2, 8, 9, 15, and 16: 27 mg/m²
• Cycle 13 and Beyond:
  • Days 1, 2, 15, and 16: 27 mg/m²

The dose is given intravenously over 10 minutes. One cycle is a total of 28 days. The treatment is continued until either the disease shows signs of progression or the patient develops significant side effects and can no more tolerate the drug.

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Dose of Carfilzomib (Kyprolis) monotherapy for refractory or relapsed Multiple myeloma:

• Cycle 1:
  • Day 1 and 2: 20 mg/m²
  • Days 8, 9, 15, and 16: 56 mg/m².
• Cycles 2 to 12:
  • Days 1, 2, 8, 9, 15, and 16: 56 mg/m²
• Cycle 13 and Beyond:
  • days 1, 2, 15, and 16: 56 mg/m²

The dose is given intravenously over 30 minutes. One cycle is a total of 28 days. The treatment is continued until either the disease shows signs of progression or the patient develops significant side effects and can no more tolerate the drug.

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Carfilzomib (Kyprolis) dose for refractory or relapsed Multiple myeloma along with lenalidomide and dexamethasone:

• Cycle 1:
  • Days 1 and 2: 20 mg/m²
  • Days 8, 9, 15, and 16: 27 mg/m²
• Cycles 2 to 12:
  • Days 1, 2, 8, 9, 15, and 16: 27 mg/ m²
• Cycles 13 to 18:
  • Days 1, 2, 15, and 16: 27 mg/m²

Each cycle is of 28 days. A single dose of Carfilzimib is administered over at least 10 minutes.

Continue Lenalidomide and dexamethasone after cycle 18 until the patient is no more tolerating it or the disease shows signs of progression. Discontinue carfilzomib.

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Carfilzomib (Kyprolis) dose for refractory or relapsed Multiple myeloma along with dexamethasone:

• Cycle 1:
  • Days 1 and 2: 20 mg/m² administered over 10 minutes
  • Days 8, 9, 15, and 16: 56 mg/m² over 30 minutes
• Cycle 2 and Beyond:
  • Days 1, 2, 8, 9, 15, and 16: 56 mg/m² over 30 minutes 

The treatment may be continued until the patient can no more tolerate it or the disease shows signs of progression.

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Carfilzomib (Kyprolis) dose for refractory or relapsed Multiple myeloma along with dexamethasone:

• Cycle 1:
  • Day 1: 20 mg/m² administered over 30 minutes
  • Days 8 and 15: 70 mg/m² over 30 minutes.
• Cycle 2 and Beyond:
  • Days 1, 8, and 15: 70 mg/m² over 30 minutes.

One cycle is a total of 28 days. The treatment is continued until either the disease shows signs of progression or the patient develops significant side effects and can no more tolerate the drug.

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Carfilzomib (Kyprolis) dose for Waldenström macroglobulinemia:

• Induction phase: Cycle 1:
  • Days 1, 2, 8, and 9 of a 21-day treatment cycle: 20 mg/m² over 20 minutes (along with dexamethasone and rituximab).
• Cycles 2 - 6:
  • Days 1, 2, 8, and 9 of a 21-day treatment cycle: 36 mg/m² over 30 minutes (along with dexamethasone and rituximab)
• Maintenance Phase:
  • Begins 8 weeks after the induction therapy. It is continued only if a good response is observed and the disease is stable.
  • Days 1 and 2 every 8 weeks for 8 cycles: 36 mg/m² over 30 minutes (along with dexamethasone and rituximab).

Use in Children:

Not applicable

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Carfilzomib (Kyprolis) Pregnancy Risk Factor D

Carfilzomib if given to pregnant women can cause severe fetal harm. A pregnancy test should be done on all women of childbearing years before initiating therapy.

Patients should also follow strict contraception throughout therapy and for at least six months after their last Carfilzomib dose. Effective contraception should be used for at least three months while on treatment, and at least three months after the last dose.

It can also lead to impaired fertility in males as well as females.

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Carfilzomib (Kyprolis) dose in renal impairment:

Patients with Preexisting renal impairment and on hemodialysis:

• Dosage adjustment is not necessary. Monitor the dose after dialysis.

Renal toxicity during treatment: (Serum creatinine more than 2 times the baseline, CrCl less than 15 mL/minute, or CrCl decreases to less than half of the baseline, or the patient needs dialysis):

• Withhold the dose and monitor renal function.
• Resume the dose when the renal function has improved to within 25% of baseline.

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Carfilzomib (Kyprolis) dose in hepatic impairment:

Patients with preexisting liver disease:

Reduce the dose of Carfilzomib dose by one-fourth if there is mild or moderate hepatic impairment:

Mild impairment is defined as:

• Total bilirubin 1 - 1.5 times the ULN and any AST or
• Total bilirubin is normal but AST is more than the ULN

Moderate hepatic impairment is defined as:

• Total bilirubin more than 1.5 - 3 times the ULN and any AST

Severe hepatic impairment is defined as:

• Bilirubin level greater than 3 times the ULN.

Deranged LFTs during treatment:

Grade 3 or 4 elevation of bilirubin, transaminases, or other liver function abnormalities:

• Withhold the treatment until the LFTs have returned to normal.
• The dose may then be restarted at a lower dose. Strict monitoring of liver functions is necessary in such cases.

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Common Side Effects Of Carfilzomib (Kyprolis):

System	Common Side Effects	Uncommon Side Effects	Rare Side Effects
Cardiovascular	Hypertension, Peripheral edema, Chest pain	Deep vein thrombosis, Pulmonary embolism, Pulmonary hypertension, Ischemic heart disease	Cardiac failure, Hypertensive crisis, Hypotension, Thromboembolic complications
Central nervous system	Fatigue, Chills, Headache, Insomnia, Dizziness, Hypoesthesia, Peripheral neuropathy	Paresthesia, Peripheral sensory neuropathy	Anxiety, Intracranial hemorrhage, Pain, Voice disorder
Gastrointestinal and liver-related	Nausea, Vomiting, Diarrhea, Anorexia, Constipation	Abdominal pain, Dyspepsia, Gastrointestinal hemorrhage, Toothache, Upper abdominal pain	Dyspepsia, Gastrointestinal hemorrhage, Toothache, Upper abdominal pain, Hepatic failure, Increased serum transaminases
Hematologic & oncologic, infections	Thrombocytopenia, Anemia, Lymphocytopenia, Leukopenia, Neutropenia	Febrile neutropenia	Sepsis, influenza
Neuromuscular & skeletal	Back pain, Muscle spasm	Arthralgia, Asthenia, Limb pain	Arthralgia, Asthenia, Limb pain, Musculoskeletal chest pain, Musculoskeletal pain, Myalgia
Renal	Increased serum creatinine	Renal insufficiency, Acute renal failure, Renal failure syndrome	Urinary tract infection,
Respiratory	Dyspnea, Cough, Upper respiratory tract infection, Pneumonia	Acute respiratory distress syndrome, Acute respiratory failure, Interstitial pulmonary disease, Pneumonitis	Bronchitis, Bronchopneumonia, Epistaxis, Nasopharyngitis, Oropharyngeal pain, Pulmonary edema, Pulmonary infection, Respiratory tract infection, Rhinitis
Endocrine & metabolic		Hypercalcemia, Hyponatremia, Hypophosphatemia	Hyperglycemia, Hyperkalemia, Hyperuricemia, Hypoalbuminemia, Hypocalcemia, hypokalemia, hypomagnesemia
Miscellaneous	Fever		Multiorgan failure, Blurred vision, Cataract, Infusion site reaction, Erythema,  Hyperhidrosis, Pruritus, Skin rash

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Contraindications to Carfilzomib (Kyprolis):

Allergy reactions to any component of the drug or the drug itself

Warnings and Precautions

• Bone marrow suppression:

Bone marrow suppression can occur manifesting as cytopenias. Thrombocytopenia can be severe enough to require transfusion support or withholding therapy. Cytopenias, especially thrombocytopenias, should be closely monitored.

• Cardiovascular effects

Carfilzomib has been linked to pulmonary edema. This can be a new-onset, or worsening, of heart failure. It also causes decreased left ventricular Ejection fraction.

Restrictive cardiomyopathy has been reported. Myocardial infarction may also occur. Drug-induced cardiac complications can be dangerous for older patients and people with preexisting heart disease.

During therapy, patients should be closely observed. Cardiac arrest has been reported within 24 hours of the infusion during the induction phase.

• Hemorrhage

It is possible to have fatal or serious bleeding diathesis, with or without thrombocytopenia. It is important to monitor patients and advise them to discontinue treatment or reduce their dose.

• Hypertension

It is important to control hypertension before you start treatment. Hypertension can lead to a hypertensive emergency or crisis.

• Infusion reactions

Pre-medicating patients is important before the treatment, as it could cause life-threatening reactions. Infusion reactions can manifest as fever, myalgia, and flushing when mild.

• PRES (posterior reversible encephalopathy syndrome):

Posterior irreversible encephalopathy syndrome (PRES) can occur during the treatment. It may manifest as seizures, headaches, lethargy and blindness, confusion, altered awareness, hypertension, and other neurological disorders.

Treatment discontinuation and appropriate therapy should be instituted.

• Pulmonary toxicity:

Pulmonary toxicity can occur during the treatment. Patients may develop:

• Acute respiratory distress syndrome (ARDS).
• Acute respiratory failure
• Interstitial lung disease.
• Pneumonitis
• Pulmonary Hypertension

Patients who develop shortness of breath or cough should be investigated and managed appropriately and on an urgent basis. Until the symptoms resolve, Carfilzomib treatment should be stopped.

• Nephrotoxicity:

Patients at high risk for developing renal failure, especially those with baseline renal impairment, should have their renal function monitored.

• Thrombotic microangiopathy

Patients receiving Carfilzomib therapy may develop thrombotic microangiopathy (hemolytic uremic syndrome or thrombotic thrombocytopenic purpura)

If the patient is diagnosed with TTP or HUS, the treatment should be stopped and appropriate management should be started.

• Thromboembolic events:

Patients receiving combination therapy with dexamethasone and/or lenalidomide with Carfilzomib are at increased risk of developing DVT and venous thrombosis. The risk of thrombosis is also high in women who are using oral hormonal contraceptive pills.

High-risk patients should be given prophylactic thromboprophylaxis such as Enoxaparin, Heparin, Apixaban, or Rivaroxaban.

• Tumor lysis syndrome (TLS)

Tumor lysis syndrome is a serious condition resulting from the breakdown of a large number of cells all of a sudden. Those who have a high tumor burden are more at risk of developing TLS.

To prevent the development of TLS, patients should be properly hydrated before treatment initiation. During the treatment, monitoring for TLS is important as it is preventable with hydration and simple measures. Rasburicase or other drugs may be added before the treatment. 

• Hepatic impairment

Patients with mild or moderate preexisting liver impairment should be watched for worsening LFTs. Close monitoring is recommended.

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Monitoring Parameters:

• CBC with differential and platelets
• Serum potassium levels
• Renal function
• Pulmonary function
• Liver function tests
• Blood pressure
• Pregnancy test in women of reproductive potential before treatment.
• Monitor for injection-related reactions and for signs suggestive of:
  • Heart failure
  • Tumor lysis syndrome (TLS)
  • Peripheral neuropathy
  • PRES
  • TTP and HUS, and 
  • Thrombosis

How to administer Carfilzomib (Kyprolis)?

It should be administered intravenously between 10 and 30 minutes, depending on the regimen. Avoid intravenous pushes or bolus administration.

Before initiating the first cycle, it is important that the patient be adequately hydrated. Intravenous Hydration should continue with 250-500 mL of NS before (recommended) as well as after (if necessary) each dose in Cycle 1.

Before and after administration of carfilzomib, flush the infusion line with 0.9% saline (or 5% Dextrose) immediately.

Avoid giving the infusion with any other medication. In addition, pre-medicate the patient with dexamethasone 4mg orally or intravenous when you infuse carfilzomib for more than ten minutes, or with dexamethasone 8mg orally, intravenous when you infuse carfilzomib for more than thirty minutes.

Mechanism of action of Carfilzomib (Kyprolis):

Carfilzomib inhibits proteasomes, causing cell cycle arrest and apoptosis. (Proteasomes control intracellular protein homeostasis).

It is specifically a powerful and irreversible inhibitor for the chymotrypsin-like activity of the 20S proteasome, which is selectively targeted by the drug.

Protein-binding: 97%

Half-life: within 1 hour

Metabolism: Extensive

Excretion: Urine.

Carfilzomib Available Brand Names:

Kyprolis (Onyx Pharmaceuticals)

Carfilzomib (Kyprolis) Brand Names in Pakistan:

No brands available in Pakistan.