CARFDEXA+ISAT; CARFDEXA(W)+ISAT

^The dexamethasone dose should be reduced in elderly patients ≥ 75 years of age.

^#In the clinical trial, dexamethasone was administered first, followed by isatuximab, and then carfilzomib.

^§For patients with BSA > 2.2 m², carfilzomib should be dosed based on a maximum BSA of 2.2 m².

*In the Arrow study, dexamethasone was given on Days 1, 8, and 15 for Cycle 10 onwards.

REPEAT EVERY 28 DAYS

Until disease progression or unacceptable toxicity

• Also refer to CCO Antiemetic Summary
   

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.

Pre-medications (prophylaxis for infusion reaction (IR)):

To be given 15-60 minutes prior to isatuximab infusion:

• Dexamethasone IV/PO as per regimen*^
• Acetaminophen 650-1000 mg PO (or equivalent)
• Diphenhydramine 25-50 mg IV/PO (or equivalent)^†
• H2 antagonist

In the IKEMA study, pre-medications for isatuximab were re-considered if no reactions occurred after 4 consecutive doses.

_{^*Dexamethasone is part of combination therapy; the treatment dose will serve as pre-medication on infusion days. Additional corticosteroids are not required as pre-medication on infusion days when dexamethasone is given. Decrease dexamethasone dose in patients > 75 years old.} 

_{^Give dexamethasone IV on the days of isatuximab and/or carfilzomib administration and PO on the other days (based on isatuximab product monograph).}

_{^†IV preferred for at least the first 4 infusions.}
 

On carfilzomib treatment days, dexamethasone should be given at least 30 minutes, but no more than 4 hours before carfilzomib.
 

Doses should be modified according to the protocol by which the patient is being treated.

Hypertension should be well-controlled prior to initiation of treatment with carfilzomib.

Carfilzomib doses do not need to be re-calculated for weight changes ≤ 20%.
 

Dose Levels for Carfilzomib: 

Dose Modifications:

Dexamethasone doses may be held or reduced for dexamethasone-related adverse events (e.g. hyperglycemia, fluid retention) to improve tolerability.

Dose reductions are not recommended for isatuximab. Doses may be delayed or discontinued in case of neutropenia or IRs.

In a pharmacokinetic study, carfilzomib AUC increased by 50% in patients with baseline mild or moderate hepatic impairment compared to those with normal hepatic function. The incidence of serious adverse events was higher in patients with hepatic impairment as well.
 

No dosage adjustment required for dexamethasone or isatuximab.

No starting dose adjustment is required for carfilzomib in patients with baseline renal impairment. For patients on dialysis receiving carfilzomib, administer dose after dialysis.

The dexamethasone dose should be reduced in elderly patients.

There was a higher incidence of certain adverse effects (including cardiac failure) observed in patients > 65 years of age, especially in those > 75 years of age treated with carfilzomib.

Refer to isatuximab, carfilzomib drug monograph(s) for additional details of adverse effects.

Refer to isatuximab, carfilzomib drug monograph(s) for additional details.

• Caution with P-glycoprotein substrates (i.e. verapamil, digoxin, morphine, ondansetron) and monitor digoxin levels when given with carfilzomib.

• Caution and consider non-hormonal method(s) of contraception as use of oral contraceptives or other hormonal methods of contraception may have reduced efficacy and may increase the risk of blood clots.

• Isatuximab interferes with the indirect antiglobulin (Coombs) test by binding to CD38 on RBCs. Patient's blood should be typed and screened, and RBC genotyped prior to initiating treatment. Notify blood transfusion centres of this in the event of a planned transfusion and educate patients. 

• Isatuximab may interfere with the serum protein electrophoreses (SPE) and immunofixation (IFE) assays used to monitor M-protein. This can impact the monitoring of response and disease progression in some patients with IgG kappa myeloma protein.

Refer to isatuximab, carfilzomib drug monograph(s) for additional details.

​​​​​​Administration: dexamethasone

• Oral self-administration or may be given by IV route on carfilzomib clinic days.
• Dexamethasone IV/PO should be given at least 30 minutes, but no more than 4 hours before carfilzomib.
• Give tablets with food, preferably in the morning.
   

Administration: Isatuximab

• Refer to Infusion Rate table below.
• Dilute with 250 mL of NS or D5W.
• The infusion bag must be made of polyolefins (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) with di (2-ethylhexyl) phthalate (DEHP) or ethyl vinyl acetate (EVA).
• Mix by gently inverting the bag. Do not shake.
• Administer by IV infusion using an IV tubing infusion set (in polyethylene [PE], polyvinyl chloride [PVC] with or without di (2-ethylhexyl) phthalate [DEHP], polybutadiene [PBD] or polyurethane [PU]) with an in-line filter (polyethersulfone [PES], polysulfone or nylon).
• Do not infuse concomitantly in the same IV line with other agents.
• Store unopened vials between 2 to 8°C (36°F to 46°F). Protect from light.
   

Infusion Rate for Isatuximab

Isatuximab should be administered at the initial infusion rate with incremental escalation as described below. Infusion rate escalations should only be considered in the absence of infusion-related reactions (IRs).

Administration: carfilzomib

• Reconstitute vials with Sterile Water for Injection. Volume for reconstitution depends on vial size; refer to product monograph for instructions.
• After reconstitution, gently swirl and/or invert the vial slowly for 1 minute. Do not shake.
• If foaming occurs, allow the solution to settle in the vial until foaming subsides (approximately 5 minutes) and the solution is clear, colourless and free of visible particulates.
• May further dilute dose in 50-100 mL D5W. Do not dilute in NS for IV administration.
• DO NOT administer as an IV bolus. May be administered directly by IV infusion or in an IV bag.
• Do not mix with or administer as an infusion with other medications.
• Infuse over 30 minutes for regimens with a usual dose of 56 mg/m² and 70 mg/m². Keep infusion time consistent during treatment regardless of any dose modifications.
• Flush line with NS or D5W before and after carfilzomib administration . 
• If a dose is missed, a minimum of 5 days between doses is required for once weekly dosing.
• Store unopened vials refrigerated at 2–8°C in original package and protected from light. Reconstituted or diluted drug do not require protection from light during administration.
   

Contraindications

• Patients who have a hypersensitivity to these drug or any of their components
   

Warnings/Precautions

• Use carfilzomib with caution in patients on a controlled sodium diet. Each mL of the reconstituted carfilzomib solution contains 0.3 mmols (7 mg) of sodium.
• The risk of heart failure is increased in elderly patients (≥ 75 years). Patients with NYHA Class III/IV heart failure, recent MI, conduction abnormalities, angina or arrhythmias uncontrolled by medications were not eligible for carfilzomib-based clinical trials. These patients may be at greater risk of cardiac complications and should have their medical management optimized, including hypertension, prior to starting treatment with carfilzomib and monitored closely throughout.
• Patients with primary refractory disease or who progressed or were refractory to anti-CD38 treatment were excluded from isatuximab clinical trials.
• Patients should use caution when driving or using machinery as fatigue, dizziness and a drop in blood pressure may occur with carfilzomib treatment.
   

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
 

Recommended Clinical Monitoring

Suggested Clinical Monitoring

Dexamethasone PO - Outpatient prescription for home administration

CADTH Reimbursement Recommendation: Isatuximab (Sarclisa). Canadian Journal of Health Technologies. February 2022.

CARFDEXA regimen monograph, Ontario Health (Cancer Care Ontario).

Carfilzomib drug monograph, Ontario Health (Cancer Care Ontario).

Isatuximab drug monograph, Ontario Health (Cancer Care Ontario).

Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet 2021; 397: 2361–71.

Moreau P, Mateos MV, Berenson JR, et al. 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. 2018 Jul;19(7):953-964.

• Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline