isatuximab (Rx)

Adverse reactions occurred in combination with pomalidomide and dexamethasone

>10%

All grades

• Anemia (99%)
• Neutropenia (96%)
• Lymphopenia (92%)
• Thrombocytopenia (84%)
• Upper respiratory tract infection (57%)
• Infusion-related reactions (38%)
• Pneumonia (31%)
• Diarrhea (26%)
• Dyspnea (17%)
• Nausea (15%)
• Vomiting (12%)
• Febrile neutropenia (12%)

Grade 3-4

• Neutropenia (24-61%)
• Lymphopenia (13-42%)
• Anemia (32%)
• Pneumonia (3.3-22%)
• Thrombocytopenia (14-16%)
• Febrile neutropenia (1.3-11%)

1-10%

Grade 3-4

• Upper respiratory tract infections (9%)
• Dyspnea (5%)
• Diarrhea (2%)
• Infusion-related reactions (1.3%)
• Vomiting (1.3%)

Contraindications

Severe hypersensitivity to isatuximab or to any of its excipients

Cautions

Can cause fetal harm

Neutropenia

• Neutropenia reported
• Monitor complete blood cell counts periodically during treatment
• Consider antibacterial and antiviral prophylaxis during treatment
• Monitor patients with neutropenia for signs of infection
• If grade 4 neutropenia occurs, delay dose until neutrophil count recovery to at least 1 x 109/L, and provide supportive care with growth factors, according to institutional guidelines

Second primary malignancies

• Reported increased incidence of second primary malignancies in patients treated with isatuximab-containing regimens
• Most common (≥1%) second primary malignancies included skin cancers (5% with isatuximab-containing regimens and 2.6% with comparative regimens) and solid tumors other than skin cancer (3% with isatuximab-containing regimens and 1.8% with comparative regimens)
• Patients with non-melanoma skin cancer continued treatment after resection of skin cancer
• Monitor developing second primary malignancies

Infusion-related reactions

• Serious infusion-related reactions including life-threatening anaphylactic reactions have occurred with treatment; severe signs and symptoms have included cardiac arrest, hypertension, hypotension, bronchospasm, dyspnea, angioedema, and swelling
• All infusion-related reactions started during the first infusion and resolved within the same day
• Premedicate before infusion to decrease the risk and severity of the reactions; monitor vital signs frequently during the entire infusion
• For Grade 1 or 2 reactions, interrupt infusion and provide appropriate medical support
• If symptoms improve, restart infusion and reduce rate by half, with supportive care as needed, and closely monitor
• If symptoms do not recur after 30 min, then increase infusion rate to the initial rate, and then increase incrementally
• In case symptoms do not improve or recur after interruption, permanently discontinue and institute appropriate management
• Permanently discontinue therapy if a grade 3 or higher infusion-related reaction occurs and institute appropriate medical management

Drug interaction overview

• Serological testing (indirect antiglobulin test)

  • Isatuximab binds to CD38 on red blood cells (RBCs) and may result in a false-positive indirect antiglobulin test (indirect Coombs test)
  • Type and screen patients before starting treatment
  • Inform blood bank that the patient is receiving isatuximab
  • If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given as per local blood bank practices

• Serum protein electrophoresis and immunofixation tests

  • Isatuximab is an IgG kappa monoclonal antibody that can be incidentally detected on both serum protein electrophoresis and immunofixation assays used for clinical monitoring of endogenous M-protein
  • This interference may affect the accuracy of the determination of complete response in some patients with IgG kappa myeloma protein
  • In patients with persistent very good partial response, where interference is suspected, consider using an FDA-cleared isatuximab-irfc-specific IFE assay to distinguish isatuximab from any remaining endogenous M protein in patient’s serum to facilitate determination of a complete response

Pregnancy

Based on the mechanism of action, fetal harm may occur when isatuximab is administered to a pregnant woman

No data available on use in pregnant women to evaluate drug-associated risks

Animal reproduction toxicity studies have not been conducted

Clinical considerations

• IgG1 monoclonal antibodies are known to cross the placenta

• Based on its mechanism of action, isatuximab may cause depletion of fetal CD38-positive immune cells and decrease bone density monoclonal antibodies are known to cross the placenta

Contraception

• Females: advise females of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose
• Also see prescribing information for pomalidomide for further information

Lactation

Data not available on presence of isatuximab in human milk, on milk production, or effects on the breastfed child

Maternal IgF is known to be present in human milk; effects of local gastrointestinal exposure in the breastfed infant are unknown

Advise lactating women not breastfeed during treatment

Refer to the prescribing information of pomalidomide and dexamethasone for further recommendations

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Anti-CD38 monoclonal antibody; monoclonal antibody that targets a specific epitope on the CD38 receptor on plasma cells that promote apoptosis and immunomodulatory activity

Absorption

Peak plasma concentration: 351 mcg/mL

AUC: 72,600 mcg⋅hr/hr

Median steady-state reached at 8 weeks

Distribution

Vd: 8.13 L

Metabolism

Expected to metabolized into small peptides by catabolic pathways

Elimination

At steady-state, the near elimination (≥99%) of isatuximab from plasma after last dose is predicted to occur in ~2 months

IV Incompatibilities

Do not administer concomitantly in the same IV line with other agents

IV Compatibilities

0.9% NaCl

Dextrose 5% (D5W)

IV Preparation

Calculate dose required based on actual body weight

Visual inspect parenteral drug products for particulate matter and discoloration before administration

Remove the same volume of diluent from 0.9% NaCl or D5W diluent bag as the required volume of isatuximab

Withdraw the necessary volume of isatuximab and add to the 0.9% NaCl or D5W infusion bag

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)

Gently invert bag to mix; do not shake

IV Administration

Administer by IV infusion using an IV tubing infusion set (in PE, PVC with or without DEHP, polybutadiene [PBD], or polyurethane [PU]) with a 0.22-micron in-line filter (polyethersulfone [PES], polysulfone, or nylon)

Premedications

• Administer 15-60 min before infusion

• Combination with pomalidomide

  • Dexamethasone 40 mg PO/IV (or 20 mg PO/IV for patients aged ≥75 years)
  • Acetaminophen 650-1000 mg PO (or equivalent)
  • Diphenhydramine 25-50 mg PO/IV (or equivalent); IV route is preferred for at least the first 4 infusions
  • Total dose of dexamethasone dose is to be administered only once before infusion as part of premedication and of treatment, before isatuximab and pomalidomide administration

• Combination with carfilzomib

  • Dexamethasone 20 mg (IV on days of isatuximab and/or carfilzomib infusions, PO on day 22 in cycle 2 and beyond, and PO on day 23 in all cycles)
  • Acetaminophen 650-1000 mg PO (or equivalent)
  • Diphenhydramine 25-50 mg PO/IV (or equivalent); IV route is preferred for at least the first 4 infusions
  • Total dose of dexamethasone dose is to be administered only once before infusion as part of premedication and of treatment, before isatuximab and carfilzomib administration

Infusion rate H4

• Consider incremental escalation of the infusion rate only in the absence of infusion-related reactions
• First IV infusion: Start 25 mL/hr; if no reaction after 60 min, increase by 25 mL/hr q30min, not to exceed 150 mL/hr
• Second IV infusion: Infuse at 50 mL/hr; if no reaction after 30 min, increase by 50 mL/hr for 30 min then increase by 100 mL/hr q30min; not to exceed 200 mL/hr
• Subsequent IV infusions: Infuse at 200 mL/hr; not to exceed 200 mL/hr

Missed dose

• If planned dose is missed, administer dose as soon as possible
• Adjust treatment schedule accordingly, maintain treatment interval

Storage

Unused vials: Refrigerate at 2-8ºC (36-46ºF); do not shake and protect from light

Diluted solutions: Refrigerate at 2-8ºC for up to 48 hr, followed by 8 hr (including infusion time) at room temperature