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Multiple myeloma KCd (carfilzomib CYCLOPHOSPHamide and dexamethasone)

This protocol is based on limited evidence; refer to the evidence section of this protocol for more information.

Patients with myeloma should be considered for inclusion into clinical trials. Link to ALLG website opens in a new tab or window and ANZCTR website opens in a new tab or window.

Link to Medical Scientific Advisory Group (MSAG) Clinical Practice Guideline Multiple Myeloma opens in a new tab or window

Link to MyeTxScheduler opens in a new tab or window developed by Myeloma Specialist Practice Network of the Haematology Society of Australia and New Zealand Nurses Group

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Cycle 1

Drug Dose Route Day
Dexamethasone 20 mg * IV/PO 1 and 2, 8 and 9, 15 and 16, 22 and 23
CYCLOPHOSPHamide 300 mg/m2 (Cap dose at 500 mg) PO ** 1, 8, 15
Carfilzomib 20 mg/m2 *** (Cap dose at 44 mg) IV 1 and 2
Carfilzomib 36 mg/m2 *** (Cap dose at 79.2 mg) IV 8 and 9 and 15 and 16

Cycle 2 and further cycles

Drug Dose Route Day
Dexamethasone 20 mg * IV/PO 1 and 2, 8 and 9, 15 and 16, 22 and 23
CYCLOPHOSPHamide 300 mg/m2 (Cap dose at 500 mg) PO ** 1, 8, 15
Carfilzomib 36 mg/m2 *** (Cap dose at 79.2 mg) IV 1 and 2, 8 and 9, 15 and 16

* Dexamethasone dose and schedule can be adjusted at clinician’s discretion.1, 2
** Dosing may require rounding to nearest tablet strength to enable delivery of a measurable dose. Cyclophosphamide can also be administered intravenously.
*** Patients with a body surface area > 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustment required when weight changes > 20%.

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity.
Notes:

It is the consensus of the reference committee that a 20 mg/week starting dose of dexamethasone should be considered in patients > 75 years.3 

Drug status:

Carfilzomib: (PBS authority opens in a new tab or window)

Cyclophosphamide and dexamethasone is on the PBS general schedule opens in a new tab or window

Dexamethasone is available as 4 mg and 0.5 mg tablets

Cost:
~ $15,120 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1

Day 1
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
CYCLOPHOSPHamide 300 mg/m2 (PO) (Cap dose at 500 mg) ONCE a week on days 1, 8, and 15. Take in the morning.**
Carfilzomib 20 mg/m2 (IV) (Cap dose at 44 mg) in 100 mL glucose 5% over 30 minutes ***
Day 2
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
Carfilzomib 20 mg/m2 (IV) (Cap dose at 44 mg) in 100 mL glucose 5% over 30 minutes ***
Day 8
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
CYCLOPHOSPHamide 300 mg/m2 (PO) (Cap dose at 500 mg) ONCE a week on days 1, 8, and 15. Take in the morning.**
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 9
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 15
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
CYCLOPHOSPHamide 300 mg/m2 (PO) (Cap dose at 500 mg) ONCE a week on days 1, 8, and 15. Take in the morning.**
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 16
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 22 and 23
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*

Cycle 2 and further cycles

Day 1
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
CYCLOPHOSPHamide 300 mg/m2 (PO) (Cap dose at 500 mg) ONCE a week on days 1, 8, and 15. Take in the morning.**
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 2
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 8
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
CYCLOPHOSPHamide 300 mg/m2 (PO) (Cap dose at 500 mg) ONCE a week on days 1, 8, and 15. Take in the morning.**
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 9
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 15
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
CYCLOPHOSPHamide 300 mg/m2 (PO) (Cap dose at 500 mg) ONCE a week on days 1, 8, and 15. Take in the morning.**
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 16
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 22 and 23
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*

* Dexamethasone dose and schedule can be adjusted at clinician’s discretion.1, 2
** Dosing may require rounding to nearest tablet strength to enable delivery of a measurable dose. Cyclophosphamide can also be administered intravenously.
*** Patients with a body surface area > 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustment required when weight changes > 20%.

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity.

Cycle 1

Drug Dose Route Day
Dexamethasone 20 mg * IV/PO 1 and 2, 8 and 9, 15 and 16, 22 and 23
CYCLOPHOSPHamide 300 mg/m2 (Cap dose at 500 mg) PO ** 1, 8, 15
Carfilzomib 20 mg/m2 *** (Cap dose at 44 mg) IV 1 and 2
Carfilzomib 36 mg/m2 *** (Cap dose at 79.2 mg) IV 8 and 9 and 15 and 16

Cycle 2 and further cycles

Drug Dose Route Day
Dexamethasone 20 mg * IV/PO 1 and 2, 8 and 9, 15 and 16, 22 and 23
CYCLOPHOSPHamide 300 mg/m2 (Cap dose at 500 mg) PO ** 1, 8, 15
Carfilzomib 36 mg/m2 *** (Cap dose at 79.2 mg) IV 1 and 2, 8 and 9, 15 and 16

* Dexamethasone dose and schedule can be adjusted at clinician’s discretion.1, 2
** Dosing may require rounding to nearest tablet strength to enable delivery of a measurable dose. Cyclophosphamide can also be administered intravenously.
*** Patients with a body surface area > 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustment required when weight changes > 20%.

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity.
Notes:

It is the consensus of the reference committee that a 20 mg/week starting dose of dexamethasone should be considered in patients > 75 years.3 

Drug status:

Carfilzomib: (PBS authority opens in a new tab or window)

Cyclophosphamide and dexamethasone is on the PBS general schedule opens in a new tab or window

Dexamethasone is available as 4 mg and 0.5 mg tablets

Cost:
~ $15,120 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1

Day 1
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
CYCLOPHOSPHamide 300 mg/m2 (PO) (Cap dose at 500 mg) ONCE a week on days 1, 8, and 15. Take in the morning.**
Carfilzomib 20 mg/m2 (IV) (Cap dose at 44 mg) in 100 mL glucose 5% over 30 minutes ***
Day 2
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
Carfilzomib 20 mg/m2 (IV) (Cap dose at 44 mg) in 100 mL glucose 5% over 30 minutes ***
Day 8
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
CYCLOPHOSPHamide 300 mg/m2 (PO) (Cap dose at 500 mg) ONCE a week on days 1, 8, and 15. Take in the morning.**
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 9
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 15
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
CYCLOPHOSPHamide 300 mg/m2 (PO) (Cap dose at 500 mg) ONCE a week on days 1, 8, and 15. Take in the morning.**
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 16
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 22 and 23
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*

Cycle 2 and further cycles

Day 1
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
CYCLOPHOSPHamide 300 mg/m2 (PO) (Cap dose at 500 mg) ONCE a week on days 1, 8, and 15. Take in the morning.**
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 2
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 8
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
CYCLOPHOSPHamide 300 mg/m2 (PO) (Cap dose at 500 mg) ONCE a week on days 1, 8, and 15. Take in the morning.**
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 9
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 15
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
CYCLOPHOSPHamide 300 mg/m2 (PO) (Cap dose at 500 mg) ONCE a week on days 1, 8, and 15. Take in the morning.**
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 16
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*
Carfilzomib 36 mg/m2 (IV) (Cap dose at 79.2 mg) in 100 mL glucose 5% over 30 minutes ***
Day 22 and 23
Dexamethasone 20 mg (IV/PO) On days 1, 2, 8, 9, 15, 16, 22 and 23 with, or soon after food (30 minutes to 4 hours before carfilzomib and cyclophosphamide on days of administration).*

* Dexamethasone dose and schedule can be adjusted at clinician’s discretion.1, 2
** Dosing may require rounding to nearest tablet strength to enable delivery of a measurable dose. Cyclophosphamide can also be administered intravenously.
*** Patients with a body surface area > 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustment required when weight changes > 20%.

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity.
  • Relapsed/refractory multiple myeloma
Venous access required

IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.
A CVAD is required for the infusional chemotherapy component.

Read more about CVAD selection
Hypersensitivity/infusion related reaction

High risk with carfilzomib.

Serious hypersensitivity reactions have been reported with carfilzomib. These reactions can occur immediately following or up to 24 hours after administration of carfilzomib.

Read more about Hypersensitivity reaction
Caution with oral anti-cancer drugs

Select links for information on the safe prescribing, dispensing and administration of orally administered anti-cancer drugs. 

Read more about at COSA guidelines for the safe prescribing, dispensing and administration of systemic cancer therapy opens in a new tab or window and oral anti-cancer therapy opens in a new tab or window
Antiemetics for multi-day protocols

Patients being treated with multi-day anticancer protocols should receive antiemetics tailored to the emetogenic risk of the drugs administered each day during treatment and for two days after completion of the anticancer protocol.

No standard antiemetic regimen exists for multi-day anticancer protocols. A combination of an NK1 receptor antagonist, 5HT3, and a steroid is available on the PBS for the prevention of nausea and vomiting associated with all moderate to highly emetogenic anti-cancer therapies. 

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO every 6 hours when necessary.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Cardiac toxicity

New or worsening cardiac failure (e.g. congestive cardiac heart failure, pulmonary oedema, decreased ejection fraction), myocardial ischaemia and infarction have occurred following administration of carfilzomib. Fatal outcomes associated with cardiac failure and myocardial infarction have been reported in studies.

Elderly patients ≥ 75 years are at increased risk of cardiac failure and should be closely monitored throughout treatment.

Carfilzomib should be stopped following grade 3 or 4 cardiac events until recovery. Consideration should be given to reducing the dose of carfilzomib by 1 dose level when recommencing carfilzomib, based on an assessment of the benefit/risk.
Carfilzomib hydration

Adequate hydration should be achieved prior to each dose of carfilzomib, particularly during the first cycle. The specific pre and post hydration recommendations should be adjusted according to the treating clinician’s assessment of tumour lysis and volume overload/cardiac failure risks.
Reversible posterior leukoencephalopathy syndrome (RPLS)

Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in patients receiving this treatment and may be fatal. Discontinue drug in patients developing RPLS.

Read more about reversible posterior leukoencephalopathy syndrome (RPLS)
Pulmonary hypertension

Pulmonary hypertension has been reported in patients treated with carfilzomib.

Evaluate pulmonary hypertension as appropriate. Carfilzomib should be stopped for pulmonary hypertension until resolved or returned to baseline. The decision to restart carfilzomib should be based on a benefit/ risk assessment.  Dose modifications and/or delays may be required; for more information see the Dose modifications section below.
Hypertension

Patients may experience an increased incidence of hypertension, including hypertensive crisis with carfilzomib.

Pre-existing hypertension should be adequately controlled prior to commencing treatment and blood pressure should be monitored closely throughout treatment and then regularly as clinically indicated.  

Hypertension should be treated and if not controlled with medical management carfilzomib should be withheld until blood pressure is controlled medically. In severe or persistent hypertension, dose reduction may be necessary or permanent discontinuation should be considered.
Haemorrhage

Patients treated with carfilzomib have an increased risk of haemorrhage, including severe and sometimes fatal haemorrhagic events. Patients should be monitored for signs and symptoms of gastrointestinal, pulmonary and intracranial haemorrhage.
Pulmonary toxicity

Acute respiratory distress syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have been reported in patients receiving carfilzomib. Fatal events have occurred.

Pulmonary toxicity should be evaluated and carfilzomib should be ceased until resolved. Consideration on whether to restart carfilzomib should be based on a benefit/ risk assessment.
Bone modifying agents

Use of a bone modifying agent (BMA) should be considered in all patients with symptomatic myeloma requiring treatment. For patients with newly diagnosed symptomatic myeloma, zoledronic acid, pamidronate or denosumab should be considered for monthly administration (adjust for kidney dysfunction where appropriate) for up to 2 years. A longer duration of therapy may be appropriate (MRC M IX trial).4

For more information, please see the following protocols:
ID 137 Multiple myeloma zoledronic acid
ID 147 Multiple myeloma pamidronate
ID 3964 Multiple myeloma denosumab - note denosumab is TGA approved but not PBS reimbursed for this indication.
Bisphosphonates and dental review

Caution should be taken with prolonged use of bisphosphonates due to the risk of osteonecrosis of the jaw (ONJ). A dental review prior to treatment is recommended, and all dental issues treated before the initiation of bisphosphonates. Dental review 6 to 12 monthly during treatment is advisable to minimise risk of ONJ. Concurrent daily oral supplements of calcium 500 mg and vitamin D 400 International Units are recommended.

Read more about medication-related osteonecrosis of the jaw (MRONJ)
Peripheral neuropathy

Assess prior to each treatment. If a patient experiences grade 2 or greater peripheral neuropathy, a dose reduction, delay, or omission of treatment may be required; review by medical officer before commencing treatment.

Read more about peripheral neuropathy

Link to Anti-cancer drug induced peripheral neuropathy screening tool
Corticosteroids

Diabetic patients should monitor their blood glucose levels closely. To minimise gastric irritation, advise patient to take immediately after food. Consider the use of a H2 antagonist or proton pump inhibitor if appropriate.

Read more about acute short term effects from corticosteroids
Thromboprophylaxis

Thromboprophylaxis should be considered based on an individual benefit/risk assessment and at clinician discretion. 

Read more about the prophylaxis of venous thromboembolism (VTE) in multiple myeloma
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

Read more about prevention and management of tumour lysis syndrome.
Pneumocystis jirovecii pneumonia (PJP) prophylaxis

PJP prophylaxis is recommended e.g. trimethoprim/sulfamethoxazole 160/800 mg PO one tablet twice daily, twice weekly (e.g. on Mondays and Thursdays) OR one tablet three times weekly (e.g. on Mondays, Wednesdays and Fridays).

Read more about prophylaxis of pneumocystis jiroveci (carinii) in cancer patients
Antiviral prophylaxis

Antiviral prophylaxis is recommended.

Read more about antiviral prophylaxis drugs and doses
Growth factor support

G-CSF (short or long-acting) is available on the PBS for chemotherapy induced neutropenia depending on clinical indication and/or febrile neutropenia risk.  

Access the PBS website opens in a new tab or window
Blood tests

FBC, EUC, eGFR, LFTs, BSL, calcium and magnesium at baseline and prior to each cycle and more frequently (i.e. day 8 and 15) as clinically indicated. 
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy.

Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations

Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease. Possible suboptimal response to inactivated vaccines.

For more information about vaccinations in people with cancer refer to the Australian Immunisation Handbook opens in a new tab or window.
Fertility, pregnancy and lactation

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. There is a risk of fetal harm in pregnant women. A pregnancy test should be considered prior to initiating treatment in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and adequate contraception timeframe should be discussed with all patients of reproductive potential. Possibility of infant risk should be discussed with breastfeeding patients.

Read more about the impact of cancer treatment on fertility opens in a new tab or window
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) opens in a new tab or window unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Note: The modifications in this section are as recommended in the product information unless otherwise specified. 

Carfilzomib dose level reductions5 

Carfilzomib dose 1st dose reduction 2nd dose reduction
36 mg/m2 27 mg/m2 20 mg/m2*

 *If symptoms do not resolve, discontinue carfilzomib treatment.
Haematological toxicity
Cyclophosphamide5
ANC, Platelets x 109/L
Grade 3 haematological toxicity
 

Consider withholding cyclophosphamide

Consider dose reduction for cyclophosphamide in subsequent cycles
Grade 4 haematological toxicity Withhold cyclophosphamide. When toxicity has resolved, recommence with cyclophosphamide at a 30% reduction of the previous dose
Carfilzomib
ANC x 109/L (pre-treatment blood test)
less than 0.5 First episode

Withhold dose 

Resume at same dose level when ANC is greater than or equal to 0.5
Subsequent episodes

Withhold dose

Consider resuming at one dose decrement when ANC is greater than or equal to 0.5
Platelets x 109/L (pre-treatment blood test)

less than 10

OR

less than or equal to 30 with evidence of bleeding/bruising

First episode

Withhold dose

Resume at same dose level when platelets ≥ 10 and bleeding is controlled 

Subsequent episodes

Resume at one dose decrement when platelets ≥ 10 and bleeding is controlled 
Venous thrombosis
Greater than or equal to Grade 3

Withhold dose and commence anticoagulation

Resume at same dose level once resolved
Kidney dosing recommendations 
  • Suggested dose modifications are based on the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).
  • Where one or more drugs in a protocol is recommended to be avoided, consider using a clinically appropriate alternative treatment protocol instead.
  • Before dose adjusting or omitting a drug, consider treatment intent.
  • In kidney replacement therapy consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing. 
  • For complete information on individual drug recommendations please review the individual drug monograph in the ADDIKD guideline.
eGFR
(mL/min/1.73m2)		 Cyclophosphamide Carfilzomib*^ Dexamethasone*
≥ 60

Full dose

See table below for kidney dosing recommendations.

 

 

 

 

 

 

 

No dose reduction required in kidney dysfunction.

 

 

 

 

 

 

 

 
45 - 59

Full dose
30 - 44

Full dose
15 - 29

Full dose

Potential for increased risk of adverse events
< 15
(without kidney replacement therapy)

Consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing.
eGFR
(mL/min/1.73m2)		 Carfilzomib*^

Serum creatinine ≥ 2 x baseline 

OR

eGFR < 15 mL/min/1.73 m2 

OR

eGFR decreases to ≤ 50% of baseline 

OR 

requiring dialysis

 Withhold doses while the cause of renal dysfunction is being assessed
If attributable to carfilzomib, resume at one dose decrement when eGFR has recovered to within 25% of baseline
If not attributable to carfilzomib, resume the same dose or reduce by one dose decrement, at haematologist’s discretion, when eGFR has recovered to within 25% of baseline
For patients on dialysis receiving carfilzomib, dose is to be administered after the dialysis procedure.

* This drug was not included in the ADDIKD guideline.

^ A pharmacokinetic and safety study of carfilzomib has shown no meaningful differences in PK between patients with normal renal function and end stage renal disease.6 The carfilzomib dose schedule was not adjusted for baseline renal dysfunction in the ARROW study, but this is at the discretion of the haematologist.7
Hepatic impairment8
≥ Grade 3 elevation in LFTs (AST, ALT, or total bilirubin)

Hold carfilzomib dose until return to baseline.

If drug induced hepatotoxicity is excluded, resume carfilzomib dose at one dose decrement.

If hepatotoxicity is due to carfilzomib, discontinue treatment. 
Posterior reversible encephalopathy syndrome (PRES)8
Headaches, altered mental status, seizures, visual loss, and hypertension

If PRES is suspected, withhold carfilzomib. Consider evaluation with neuroradiological imaging for onset of visual or neurological symptoms suggestive of PRES.

If the diagnosis of PRES is excluded, resume carfilzomib at the same dose level. 

If the diagnosis is confirmed, discontinue carfilzomib. 
LVEF Reductions8

For resting LVEF < 40%

OR

reduction of LVEF to < 55% if the drop is greater than 20% from baseline

Withhold carfilzomib dose.

Resume carfilzomib at one dose decrement if: *

  • LVEF returns to ≥ 40% OR
  • LVEF returns to within 15% baseline (if withheld due to a drop to < 55%)

* Dose reduction should be attempted first to manage treatment-emergent toxicities. Schedule modification may be considered for patients who have persistent toxicities after dose reduction. 
Other non-haematologic toxicity8
Carfilzomib
≥ Grade 3

Withhold dose until toxicity has resolved to Grade 2 or less or to baseline grade.

Resume at one dose decrement
≥ Grade 3 infection

Hold carfilzomib until infection resolves. Resume carfilzomib at same dose.

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources:  

For more information see References & Disclaimer.

Carfilzomib
No specific clinically significant drug-drug interactions 
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Cyclophosphamide
  Interaction Clinical management
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Increased toxicity of cyclophosphamide possible due to increased conversion to active (and inactive) metabolites Avoid combination or monitor for cyclophosphamide toxicity
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Reduced efficacy of cyclophosphamide possible due to decreased conversion to active (and inactive) metabolites Avoid combination or monitor for decreased clinical response to cyclophosphamide
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Amiodarone Possible additive pulmonary toxicity with high-dose cyclophosphamide (i.e. doses used prior to stem cell transplant; 60 mg/kg daily or 120 to 270 mg/kg over a few days) Avoid combination or monitor closely for pulmonary toxicity
Allopurinol, hydrochlorothiazide, indapamide Delayed effect. Increased risk of bone marrow depression; probably due to reduced clearance of active metabolites of cyclophosphamide Avoid combination, consider alternative antihypertensive therapy or monitor for myelosuppression
Ciclosporin Reduced efficacy of ciclosporin due to reduced serum concentration Monitor ciclosporin levels; adjust dosage as appropriate; monitor response to ciclosporin
Suxamethonium Prolonged apnoea due to marked and persistent inhibition of cholinesterase by cyclophosphamide Alert the anaesthetist if a patient has been treated with cyclophosphamide within ten days of planned general anaesthesia
Dexamethasone
  Interaction Clinical management
CYP3A4 interactions Dexamethasone is a substrate of CYP3A4 and a weak to moderate inducer of CYP3A4. The clinical relevance of CYP3A4 induction by dexamethasone is unknown as the mechanism has yet to be established The effects of the concomitant use of dexamethasone with other CYP3A4 inducers, inhibitors or substrates is variable. If used concomitantly, monitor patients closely for adverse drug reactions
Warfarin Concurrent use may result in increased risk of bleeding or diminished effects of warfarin Monitor prothrombin time / INR (especially during initiation or discontinuation) and for signs of drug toxicity during concomitant use; adjust warfarin dose as required
Oral hypoglycaemics Corticosteroids may cause hyperglycaemia and worsen diabetes control Monitor blood glucose levels and adjust oral hypoglycaemic dose as required
General
  Interaction Clinical management
Warfarin Anti-cancer drugs may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inhibitors. If treating VTE, avoid use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window  inhibitors.

Dabigatran: avoid combination with strong P‑gp opens in a new tab or window inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Anti-cancer drugs can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and anti-cancer drug levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the anti-cancer therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update opens in a new tab or window

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter or address chemical compatibilities related to IV drug preparation and administration. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Day 1

Approximate treatment time: 2.5 to 3.5 hours

Pre treatment assessment

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Check for adverse events during previous treatment.

Anti-cancer drug patient assessment tool prior to each day of treatment.

Check observations.

Blood pressure should be assessed and monitored closely prior to and throughout treatment. 

Weigh patient.

Pre treatment medication

Verify premedication has been taken as prescribed, see treatment schedule detail for suggested premedications.

Prior to administration

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Prehydration

Intravenous hydration may be required prior to commencing treatment to reduce the incidence of tumour lysis syndrome, see drug below for more information.

Dexamethasone

Administer dexamethasone:
  • orally ONCE a day in the morning on days 1, 2, 8, 9, 15, 16, 22 and 23
  • with or immediately after food
    OR 
  • via IV infusion over 15 minutes 
  • flush with ~ 50 mL sodium chloride 0.9%
  • on the days of carfilzomib, dexamethasone should be given as a pre-treatment medication 30 minutes to 4 hours before treatment.

Note: if a dose is forgotten or vomited, contact treating team.

Cyclophosphamide

Administer cyclophosphamide:
  • orally ONCE a week in the morning on days 1, 8 and 15 every 28 days
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • patients should be well hydrated and be encouraged to void frequently during treatment to prevent cyclophosphamide induced bladder irritation. 

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Carfilzomib

Prehydration:
  • adequate hydration is required prior to cycle 1, especially in patients at high risk of tumour lysis syndrome
  • if required, administer sodium chloride 0.9% via IV infusion over 30 to 60 minutes prior to each dose in cycle 1, or as prescribed
  • patients should be monitored for fluid overload, especially those with baseline or at risk of cardiac failure.
Administer carfilzomib:
  • via IV infusion over 30 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.
Infusion-related reaction (IRR):

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency. IRRs can occur immediately following or up to 24 hours after administration of carfilzomib.

Post hydration:
  • if required, administer sodium chloride 0.9% via IV infusion over 60 minutes.

From cycle 2 onward hydration is at the discretion of the treating team.

Post administration

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions until 7 days after completion of drug(s).

Day 2

Approximate treatment time: 1.5 to 2.5 hours

Pre treatment assessment

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Check for adverse events during previous treatment.

Anti-cancer drug patient assessment tool prior to each day of treatment.

Check observations.

Blood pressure should be assessed and monitored closely prior to and throughout treatment. 

Pre treatment medication

Verify premedication has been taken as prescribed, see treatment schedule detail for suggested premedications.

Prior to administration

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Prehydration

Intravenous hydration may be required prior to commencing treatment to reduce the incidence of tumour lysis syndrome, see drug below for more information.

Dexamethasone

Administer dexamethasone:
  • orally ONCE a day in the morning on days 1, 2, 8, 9, 15, 16, 22 and 23
  • with or immediately after food
    OR 
  • via IV infusion over 15 minutes 
  • flush with ~ 50 mL sodium chloride 0.9%
  • on the days of carfilzomib, dexamethasone should be given as a pre-treatment medication 30 minutes to 4 hours before treatment.

Note: if a dose is forgotten or vomited, contact treating team.

Carfilzomib

Prehydration:
  • adequate hydration is required prior to cycle 1, especially in patients at high risk of tumour lysis syndrome
  • if required, administer sodium chloride 0.9% via IV infusion over 30 to 60 minutes prior to each dose in cycle 1, or as prescribed
  • patients should be monitored for fluid overload, especially those with baseline or at risk of cardiac failure.
Administer carfilzomib:
  • via IV infusion over 30 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.
Infusion-related reaction (IRR):

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency. IRRs can occur immediately following or up to 24 hours after administration of carfilzomib.

Post hydration:
  • if required, administer sodium chloride 0.9% via IV infusion over 60 minutes.

From cycle 2 onward hydration is at the discretion of the treating team.

Post administration

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions until 7 days after completion of drug(s).

Day 8

Approximate treatment time: 2.5 to 3.5 hours

Pre treatment assessment

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Check for adverse events during previous treatment.

Anti-cancer drug patient assessment tool prior to each day of treatment.

Check observations.

Blood pressure should be assessed and monitored closely prior to and throughout treatment. 

Pre treatment medication

Verify premedication has been taken as prescribed, see treatment schedule detail for suggested premedications.

Prior to administration

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Prehydration

Intravenous hydration may be required prior to commencing treatment to reduce the incidence of tumour lysis syndrome, see drug below for more information.

Dexamethasone

Administer dexamethasone:
  • orally ONCE a day in the morning on days 1, 2, 8, 9, 15, 16, 22 and 23
  • with or immediately after food
    OR 
  • via IV infusion over 15 minutes 
  • flush with ~ 50 mL sodium chloride 0.9%
  • on the days of carfilzomib, dexamethasone should be given as a pre-treatment medication 30 minutes to 4 hours before treatment.

Note: if a dose is forgotten or vomited, contact treating team.

Cyclophosphamide

Administer cyclophosphamide:
  • orally ONCE a week in the morning on days 1, 8 and 15 every 28 days
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • patients should be well hydrated and be encouraged to void frequently during treatment to prevent cyclophosphamide induced bladder irritation. 

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Carfilzomib

Prehydration:
  • adequate hydration is required prior to cycle 1, especially in patients at high risk of tumour lysis syndrome
  • if required, administer sodium chloride 0.9% via IV infusion over 30 to 60 minutes prior to each dose in cycle 1, or as prescribed
  • patients should be monitored for fluid overload, especially those with baseline or at risk of cardiac failure.
Administer carfilzomib:
  • via IV infusion over 30 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.
Infusion-related reaction (IRR):

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency. IRRs can occur immediately following or up to 24 hours after administration of carfilzomib.

Post hydration:
  • if required, administer sodium chloride 0.9% via IV infusion over 60 minutes.

From cycle 2 onward hydration is at the discretion of the treating team.

Post administration

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions until 7 days after completion of drug(s).

Day 9

Approximate treatment time: 1.5 to 2.5 hours

Pre treatment assessment

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Check for adverse events during previous treatment.

Anti-cancer drug patient assessment tool prior to each day of treatment.

Check observations.

Blood pressure should be assessed and monitored closely prior to and throughout treatment. 

Pre treatment medication

Verify premedication has been taken as prescribed, see treatment schedule detail for suggested premedications.

Prior to administration

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Prehydration

Intravenous hydration may be required prior to commencing treatment to reduce the incidence of tumour lysis syndrome, see drug below for more information.

Dexamethasone

Administer dexamethasone:
  • orally ONCE a day in the morning on days 1, 2, 8, 9, 15, 16, 22 and 23
  • with or immediately after food
    OR 
  • via IV infusion over 15 minutes 
  • flush with ~ 50 mL sodium chloride 0.9%
  • on the days of carfilzomib, dexamethasone should be given as a pre-treatment medication 30 minutes to 4 hours before treatment.

Note: if a dose is forgotten or vomited, contact treating team.

Carfilzomib

Prehydration:
  • adequate hydration is required prior to cycle 1, especially in patients at high risk of tumour lysis syndrome
  • if required, administer sodium chloride 0.9% via IV infusion over 30 to 60 minutes prior to each dose in cycle 1, or as prescribed
  • patients should be monitored for fluid overload, especially those with baseline or at risk of cardiac failure.
Administer carfilzomib:
  • via IV infusion over 30 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.
Infusion-related reaction (IRR):

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency. IRRs can occur immediately following or up to 24 hours after administration of carfilzomib.

Post hydration:
  • if required, administer sodium chloride 0.9% via IV infusion over 60 minutes.

From cycle 2 onward hydration is at the discretion of the treating team.

Post administration

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions until 7 days after completion of drug(s).

Day 15

Approximate treatment time: 2.5 to 3.5 hours

Pre treatment assessment

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Check for adverse events during previous treatment.

Anti-cancer drug patient assessment tool prior to each day of treatment.

Check observations.

Blood pressure should be assessed and monitored closely prior to and throughout treatment. 

Pre treatment medication

Verify premedication has been taken as prescribed, see treatment schedule detail for suggested premedications.

Prior to administration

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Prehydration

Intravenous hydration may be required prior to commencing treatment to reduce the incidence of tumour lysis syndrome, see drug below for more information.

Dexamethasone

Administer dexamethasone:
  • orally ONCE a day in the morning on days 1, 2, 8, 9, 15, 16, 22 and 23
  • with or immediately after food
    OR 
  • via IV infusion over 15 minutes 
  • flush with ~ 50 mL sodium chloride 0.9%
  • on the days of carfilzomib, dexamethasone should be given as a pre-treatment medication 30 minutes to 4 hours before treatment.

Note: if a dose is forgotten or vomited, contact treating team.

Cyclophosphamide

Administer cyclophosphamide:
  • orally ONCE a week in the morning on days 1, 8 and 15 every 28 days
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • patients should be well hydrated and be encouraged to void frequently during treatment to prevent cyclophosphamide induced bladder irritation. 

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Carfilzomib

Prehydration:
  • adequate hydration is required prior to cycle 1, especially in patients at high risk of tumour lysis syndrome
  • if required, administer sodium chloride 0.9% via IV infusion over 30 to 60 minutes prior to each dose in cycle 1, or as prescribed
  • patients should be monitored for fluid overload, especially those with baseline or at risk of cardiac failure.
Administer carfilzomib:
  • via IV infusion over 30 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.
Infusion-related reaction (IRR):

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency. IRRs can occur immediately following or up to 24 hours after administration of carfilzomib.

Post hydration:
  • if required, administer sodium chloride 0.9% via IV infusion over 60 minutes.

From cycle 2 onward hydration is at the discretion of the treating team.

Post administration

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions until 7 days after completion of drug(s).

Day 16

Approximate treatment time: 1.5 to 2.5 hours

Pre treatment assessment

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Check for adverse events during previous treatment.

Anti-cancer drug patient assessment tool prior to each day of treatment.

Check observations.

Blood pressure should be assessed and monitored closely prior to and throughout treatment. 

Pre treatment medication

Verify premedication has been taken as prescribed, see treatment schedule detail for suggested premedications.

Prior to administration

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Prehydration

Intravenous hydration may be required prior to commencing treatment to reduce the incidence of tumour lysis syndrome, see drug below for more information.

Dexamethasone

Administer dexamethasone:
  • orally ONCE a day in the morning on days 1, 2, 8, 9, 15, 16, 22 and 23
  • with or immediately after food
    OR 
  • via IV infusion over 15 minutes 
  • flush with ~ 50 mL sodium chloride 0.9%
  • on the days of carfilzomib, dexamethasone should be given as a pre-treatment medication 30 minutes to 4 hours before treatment.

Note: if a dose is forgotten or vomited, contact treating team.

Carfilzomib

Prehydration:
  • adequate hydration is required prior to cycle 1, especially in patients at high risk of tumour lysis syndrome
  • if required, administer sodium chloride 0.9% via IV infusion over 30 to 60 minutes prior to each dose in cycle 1, or as prescribed
  • patients should be monitored for fluid overload, especially those with baseline or at risk of cardiac failure.
Administer carfilzomib:
  • via IV infusion over 30 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.
Infusion-related reaction (IRR):

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency. IRRs can occur immediately following or up to 24 hours after administration of carfilzomib.

Post hydration:
  • if required, administer sodium chloride 0.9% via IV infusion over 60 minutes.

From cycle 2 onward hydration is at the discretion of the treating team.

Post administration

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions until 7 days after completion of drug(s).

Days 22 and 23

This is an oral treatment

Dexamethasone

Administer dexamethasone:
  • orally ONCE a day in the morning on days 1, 2, 8, 9, 15, 16, 22 and 23
  • with or immediately after food
    OR 
  • via IV infusion over 15 minutes 
  • flush with ~ 50 mL sodium chloride 0.9%
  • on the days of carfilzomib, dexamethasone should be given as a pre-treatment medication 30 minutes to 4 hours before treatment.

Note: if a dose is forgotten or vomited, contact treating team.

Discharge information

Discharge medications

Dexamethasone and cyclophosphamide tablets - with written instructions on how to take them.

Antiemetics - as/if prescribed.

Prophylaxis medications - as/if prescribed, i.e. antivirals, PJP prophylaxis

Patient information

Ensure patient receives protocol patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Dyspnoea
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Hypertension

High blood pressure is commonly associated with many anti-cancer drugs. Pre-existing hypertension should be controlled prior to initiation of drugs capable of causing hypertension.
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting

Early (onset days to weeks)
Cardiotoxicity

Cardiotoxicity may manifest as asymptomatic reduction in left ventricular ejection fraction (LVEF), arrhythmia, cardiomyopathy, hypertension, cardiac ischaemia and congestive heart failure (CHF). The risk of cardiotoxicity is increased by a number of factors, particularly a history of heart disease and electrolyte imbalances.

Read more about cardiotoxicity associated with anti-cancer drugs
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about immediate management of neutropenic fever
Thrombocytopenia

A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.  

Read more about thrombocytopenia
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Arthralgia and myalgia

Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation. 

Read more about arthralgia and myalgia
Constipation
Diarrhoea

Read more about treatment induced diarrhoea
Dizziness

Feeling faint or lightheaded, weak or unsteady. Advise patients to stand up slowly from sitting down or lying down positions and increase fluid intake if dehydrated.
Fatigue

Read more about fatigue
Haemorrhagic cystitis

An inflammatory process, characterised by diffuse bladder mucosal inflammation resulting in haemorrhage. Patients are at risk following blood and marrow transplant (BMT) or treatment with cyclophosphamide, ifosfamide and/or radiation therapy.

Read more about haemorrhagic cystitis
Hyperglycaemia

High blood sugar, an excess of glucose in the blood stream.
Hypokalaemia

Abnormally low levels of potassium in the blood.
Peripheral neuropathy

Typically symmetrical sensory neuropathy, affecting the fingers and toes, sometimes progressing to the hands and feet.  It is associated with several classes of anti-cancer drugs. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

Read more about peripheral neuropathy
Reversible posterior leukoencephalopathy syndrome (RPLS)

A neurological disorder which may present with headache, seizures, lethargy, confusion, blindness and/or other visual and neurological disturbances. Mild to severe hypertension may also occur.

Read more about reversible posterior leukoencephalopathy syndrome (RPLS)
Skin rash

Anti-cancer drugs can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. 

Read more about skin rash
Side effects of corticosteroids

Insomnia, oedema, increased risk of infection e.g. oral thrush, gastric irritation, worsening of peptic ulcer disease, increased blood sugar levels, loss of diabetic control, mood and behavioural changes - including anxiety, euphoria, depression, mood swings, increased appetite and weight gain, osteoporosis and fractures (long term use), bruising and skin fragility are associated with corticosteroid use.
Thromboembolism

Thromboembolic events, including pulmonary embolism, deep vein thrombosis and cerebrovascular accidents can occur. Thromboprophylaxis should be considered based on an individual benefit/risk assessment and at clinician discretion.

Read more about management of thromboembolism (VTE) in multiple myeloma

Late (onset weeks to months)
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Alopecia

Hair loss may occur from all parts of the body. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out.

Read more about alopecia and scalp cooling

Delayed (onset months to years)
Pulmonary toxicity

Pulmonary toxicity may include damage to the lungs, airways, pleura and pulmonary circulation. 

Read more about pulmonary toxicity associated with anti-cancer drugs

eviQ is currently updating the way information is presented in the evidence section to improve usability, consistency and facilitate easier update and maintenance. An updated evidence template is being implemented in a staged approach, first across new protocols, then existing protocols as they are reviewed. Find out more

Evidence for carfilzomib, cyclophosphamide and dexamethasone (KCd) in relapsed/refractory multiple myeloma (RRMM) comes from an observational study by Pennipede et al.1

This was a single-centre retrospective analysis that reviewed outcomes with KCd in 23 patients with triple-class RRMM between 2017 and 2020. Patients were given carfilzomib 20/36 mg/m2 intravenous (IV) on days 1, 2, 8, 9, 15, and 16; cyclophosphamide 300 mg/m2 IV weekly and dexamethasone 20-40 mg orally (PO) weekly that was repeated every 28 days until disease progression or toxicity. There was no comparator arm.

It should be noted that KCd plus haematopoietic stem cell transplantation (HSCT) has also been studied in the newly-diagnosed setting in transplant-eligible myeloma patients in the FORTE trial,5 as well as in patients at first relapse or refractory to no more than one line of therapy in the phase 2 MUK Five study9 as well as in patients at first relapse or refractory to no more than one line of therapy in the phase 2 MUK Five study.1

Source Study & Year Published

Supports Use
Yes/No/NA

Is the dose and regimen consistent with the protocol?
Yes/No

 Comments
Phase II trials FORTE trial 20215 NA No Newly-diagnosed, transplant-eligible MM patients; 4 cycles induction/HSCT/4 cycles consolidation; carfilzomib ​20/36 mg/m2 on Days 1, 2, 8, 9, 15 and 16; cyclophosphamide 300 mg/m2 IV on Days 1, 8 and 15, dexamethasone 20 mg PO/IV on Days 1, 2, 8, 9, 15,16, 22 and 23
  MUK Five study9 Yes No MM patients at first relapse or refractory to no more than one line of therapy; 6 cycles; cyclophosphamide 500 mg/m2 PO on Days 1, 8 and 15
Observational studies Pennipede et al. 20211 Yes Yes  
Guidelines

Date published/revised

Supports Use
Yes/No/NA

Is the dose and regimen consistent with the protocol?
Yes/No

 Comments
NCCN 14/09/2022 Yes No

Cycle 1: carfilzomib 20 mg/m2 IV on days 1-2, followed by carfilzomib 36 mg/m2 IV on days 8-9 and 15-16; cyclophosphamide 300 mg/m2 PO or IV on days 1, 8 and 15; dexamethasone 40 mg PO or IV on days 1, 8, 15 and 22

Cycles 2-9: carfilzomib 36 mg/m2 IV on days 1-2, 8-9 and 15-16; cyclophosphamide 300 mg/m2 PO or IV on Days 1, 8 and 15; dexamethasone 40 mg PO or IV on days 1, 8, 15 and 22

Maintenance cycle 10 and beyond: carfilzomib 36 mg/m2 IV on days 1-2 and 15-16
BCCA 01/06/2022 Yes No

Cycle 1: carfilzomib 20 mg/m2 on Day 1 then 70 mg/m2 on Days 8 and 15; dexamethasone 40 mg PO on days 1, 8, 15 and 22
Cycle 2 and beyond: carfilzomib 70 mg/m2 on Days 1, 8 and 15; dexamethasone 40 mg PO on days 1, 8, 15 and 22

If using: cyclophosphamide 300 mg/m2 PO on Days 1, 8 and 15
CCO October 2021 Yes No Cycle 1: carfilzomib 20 mg/m2 on Day 1 then 70 mg/m2 on Days 8 and 15; cyclophosphamide 300 mg/m2 PO on Days 1, 8, 15 and 22; dexamethasone 40 mg PO or IV on days 1, 8, 15 and 22
Cycle 2 and beyond: carfilzomib ​70 mg/m2 on Days 1, 8 and 15; cyclophosphamide 300 mg/m2 IV on Days 1, 8, 15 and 22; dexamethasone 40 mg PO or IV on days 1, 8, 15 and 22

Efficacy

Of the 23 patients analysed in the Pennipede et al.1 study, patients had received a median of six prior lines of therapy (range 3-10). All patients were triple-refractory (inclusion criteria) and 15 (65%) had penta-refractory disease. 19 (83%) had previously undergone an autologous stem cell transplant (ASCT) and 18 (78%) had received carfilzomib in the past. 13 (57%) had standard risk cytogenetics, while the remaining 10 (43%) had high-risk cytogenetics, the latter defined as the following mutations on conventional cytogenetics or fluorescence in situ hybridisation (FISH) having at any time prior to KCd treatment: del(17p), t(4;14), t(14;16), t(14;20), or 1q21 gains. Median age was 54 years (range 36-78).

In this cohort, overall response (OR) was 52%, with 26% achieving very good partial response (VGPR) and 26% achieving partial response (PR). Stable disease was seen in 22% and 26% progressed. Progression-free survival (PFS) was 4 months (3.21-7.97 95% confidence interval (CI)) and mean overall survival (OS) was 11.9 months (6.97- not reached (NR) 95% CI). Median duration of follow-up was 19.3 months (range 1-25 months) and median number of KCd cycles received was 4 (1-11).

Figure 1: Kaplan-Meier estimated PFS in all patients (n = 23)1

Figure 2: Kaplan-Meier estimated OS in all patients (n = 23)1

©European Journal of Haematology 2021

Subgroup analyses showed improved outcomes in those with standard-risk compared to high-risk cytogenetics with PFS 4.9 months (3.3-NR 95% CI) versus 3.4 months (0.93-NR 95%) and median OS 25.8 months versus 9 months, respectively.

Figure 3: Kaplan-Meier estimated PFS in standard risk (Std) patients (blue) vs high risk cytogenetics (HR) patients (yellow)1

Figure 3: Kaplan-Meier estimated OS in Std patients (blue) vs HR patients (yellow)​1

©European Journal of Haematology 2021

Toxicity

Limited safety data can be extracted from the Pennipede et al.1 study due to the small number of patients. In this pre-treated population, grade 3-4 haematological toxicities were experienced in most (74%) patients, including thrombocytopenia (61%), anaemia (61%), and neutropenia (30%). This contrasts to the safety outcomes in the larger FORTE trial5 which includes young, fit, newly-diagnosed patients, where KCd resulted in grade 3-4 haematological toxicity in only 43 of 159 (27%) of patients, with the most common being neutropenia (11%), and well-tolerated overall.

Non-haematological treatment-emergent events of any grade in the Pennipede et al.1 study included nausea (22%), febrile neutropenia (17%), diarrhoea (13%), pneumonia (13%) and cardiac events in 2 patients (9%), with two of these cardiac events being decompensated heart failure. In the FORTE trial,5 the most common grade 3-4 non-haematological toxicity was pneumonia in 6 of 159 (4%) patients. Safety data from the MUK Five study9 shows similar results (below) to FORTE,5 with the most common grade 3-4 toxicity being infection, noting that patients in this trial generally received a longer duration of therapy compared to those in Pennipede et al.1

Table 1: Adverse reactions experienced by at least 5% of participants (in either treatment arm during induction treatment) at grade 3 or above in the MUK Five study 9

©Haematologica 2021

1
Pennipede, D., G. R. Mohyuddin, R. Hawkins, et al. 2021. "Carfilzomib, cyclophosphamide, and dexamethasone (KCd) for the treatment of triple-class relapsed/refractory multiple myeloma (RRMM)." Eur J Haematol 107(6):602-608.
2
King, T. and B. Faiman. 2017. "Steroid-Associated Side Effects: A Symptom Management Update on Multiple Myeloma Treatment." Clin J Oncol Nurs 21(2):240-249.
3
Quach, H., M. H. Prince and S. Harrison on behalf of MSAG. 2022. “Clinical practice guideline multiple myeloma.” Myeloma Foundation of Australia.
4
Morgan, G. J., J. A. Child, W. M. Gregory, et al. 2011. "Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial." Lancet Oncol 12(8):743-752.
5
Gay, F., P. Musto, D. Rota-Scalabrini, et al. 2021. "Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial." Lancet Oncol 22(12):1705-1720.
6
Quach, H., D. White, A. Spencer, et al. 2017. "Pharmacokinetics and safety of carfilzomib in patients with relapsed multiple myeloma and end-stage renal disease (ESRD): an open-label, single-arm, phase I study." Cancer Chemother Pharmacol 79(6):1067-1076.
7
Moreau, P., M.V. Mateos, J.R. Berenson, et al. 2018. "Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study." Lancet Oncol 19(7):953-964.
8
Dimopoulos, M. A., P. Moreau, A. Palumbo, et al. 2016. "Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study." Lancet Oncol 17(1):27-38
9
Yong, K. L., S. Hinsley, H. W. Auner, et al. 2021. "Carfilzomib or bortezomib in combination with cyclophosphamide and dexamethasone followed by carfilzomib maintenance for patients with multiple myeloma after one prior therapy: results from a multicenter, phase II, randomized, controlled trial (MUKfive)." Haematologica 106(10):2694-2706.

Bibliography

Venner, C. P., R. LeBlanc, I. Sandhu, et al. 2021. "Weekly carfilzomib plus cyclophosphamide and dexamethasone in the treatment of relapsed/refractory multiple myeloma: Final results from the MCRN-003/MYX.1 single arm phase II trial." Am J Hematol 96(5):552-560.

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Version 2

Date Summary of changes
10/08/2023

Protocol updated with ADDIKD guideline recommendations. New kidney dosing recommendation table added to dose modification section.

PDF of previous protocol.

Version number changed to V.2
13/10/2023

Protocol reviewed by the Haematology Reference Committee. Minor formatting change made to LVEF and PRES dose modifications sections.

Review in 2 years.
06/08/2024 Timing of dexamethasone prior to administration of carfilzomib updated in treatment schedule detail to align with other carfilzomib protocols. Administration section reformatted. 

Version 1

Date Summary of changes
14/10/2022 New eviQ protocol presented at Haematology Reference Committee Meeting. Approved for publication as V.1.
Review in 1 year.

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12 Jun 2025