Isatuximab-irfc – Uses, Dosage, Side Effects, Interaction

Isatuximab (formerly SAR650984) is a humanized, IgG1-derived monoclonal antibody (mAb) produced from a Chinese hamster ovary? (CHO) cell line. Structurally, isatuximab is comprised of two identical immunoglobulin kappa light chains and two identical immunoglobulin gamma heavy chains. It is a cytolytic antibody targeted against CD38, a glycoprotein found on the surface of some immune cells that is highly expressed by malignant? plasma cells in multiple myeloma?.^[rx]Along with daratumumab, another anti-CD38 mAb, isatuximab constitutes a novel treatment modality for patients with difficult-to-treat multiple myeloma.

Following three consecutive years on the yearly “Antibodies to watch” list published in “mAb”, a peer-reviewed scientific journal dedicated to antibody research, isatuximab was granted Orphan Drug designation and approved on March 2nd, 2020, for the treatment of multiple myeloma. It is manufactured by Sanofi-Aventis U.S. under the brand name Sarclisa.^[rx]

Mechanism of action

Multiple myeloma is a blood cancer characterized by an overproduction of malignant plasma cells in the bone marrow?. A unique characteristic of myeloma cells is their dense and uniform expression of CD38 surface glycoproteins – these proteins, also expressed in relatively minor quantities on other lymphoid and myeloid cells, have been identified as performing several critical cellular functions, and this, along with their relative abundance on myeloma cells, has made them an attractive target for multiple myeloma treatment. CD38 was first identified as an activation marker, but has subsequently demonstrated roles in adhesion to endothelial CD31 proteins, as an accessory component of the synapse complex, and as an ectoenzyme involved in the metabolism of extracellular NAD+ and cytoplasmic NADP. The products of CD38’s ectoenzymatic activity include the calcium-mobilizing compound adenosine diphosphate ribose (ADPR), which can be further metabolized by CD203a/PC-1 and CD73 to adenosine, an immunosuppressive molecule that may play a role in tumor? cell evasion of the immune system.^[rx]

Isatuximab is an IgG1-derived monoclonal antibody targeted against CD38 proteins.^[rx] Its activity against CD38 results in a number of downstream effects, including direct apoptosis of the affected cell and activation of immune mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), all of which result in potent anti-tumor activity.^[rx] Via allosteric antagonism, isatuximab also inhibits CD38 ectoenzymatic activity, preventing the immunosuppressive effects of its downstream products.

Isatuximab may also exert its effects via downstream promotion of lysosome-dependent cell death, upregulation of reactive oxygen species, and restoration of antitumor immune effector cell functions.^[rx]

Isatuximab results in the apoptosis of malignant plasma cells via inhibition of a surface protein key to their survival and proliferation. It has a relatively long residence time in the body, taking approximately 2 months to clear following the final dose, and may therefore be infused on a weekly or bimonthly schedule.^[rx] Isatuximab is given in combination with pomalidomide due to a synergy that exists between the two – isatuximab can induce a depletion in host NK lymphocytes, yet the ADCC effect of anti-CD38 mAbs has been shown to be superior in patient samples with a high ratio of NK to myeloma cells. Pomalidomide, another antineoplastic agent, has the ability to induce and enhance NK lymphocyte? activity^[rx]and thus works synergistically to enhance isatuximab-mediated killing of myeloma cells.^[rx]

Isatuximab is formulated as an intravenous infusion and its administration may result in infusion-related reactions characterized most commonly by dyspnea?, cough?, chills?, and nausea?. All noted reactions started during the first infusion and 98% resolved on the same day. Reactions may be mitigated by pre-medication with acetaminophen, H2 antagonists, diphenhydramine, and/or dexamethasone.^[rx] Patients with grade 1 or 2 reactions may restart the infusion at a slower rate following the resolution of symptoms, but patients experiencing a grade 3 or higher reaction (e.g. hypertension?, bronchospasm) should discontinue therapy indefinitely.^[rx]

Isatuximab can generate false positive results for indirect antiglobulin tests (indirect Coombs tests), immunofixation tests, and serum protein electrophoresis.^[rx]

Indications

• Isatuximab is indicated in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma in adults who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.^[rx] It is also indicated in combination with carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory? multiple myeloma who have received 1 to 3 prior lines of therapy.^[rx]
• Multiple Myeloma (MM)
• Multiple Myeloma in Relapse?
• Refractory Multiple Myeloma

Use in Cancer

Isatuximab-irfc is approved to treat:

• Multiple myeloma. It is used:
  • With pomalidomide and dexamethasone in adults who have received at least two therapies, including lenalidomide and a proteasome inhibitor, or
  • With carfilzomib and dexamethasone in adults whose disease has relapsed (come back) or is refractory (does not respond to treatment) after one to three other therapies.

Isatuximab-irfc is also being studied in the treatment of other types of cancer.

Contraindications

• low levels of a type of white blood cell called neutrophils
• pregnancy
• a patient who is producing milk and breastfeeding

Dosage?

Strengths: irfc 20 mg/mL

Multiple Myeloma

IN COMBINATION WITH POMALIDOMIDE AND DEXAMETHASONE:

• Cycle 1: 10 mg/kg IV on Days 1, 8, 15, and 22 (weekly)
• Cycle 2 and beyond: 10 mg/kg IV on Days 1 and 15 (every 2 weeks)
• Each treatment cycle consists of a 28-day period.
• Therapy is repeated until the disease progresses or unacceptable toxicity.

Recommended Premedications (administer 15 to 60 minutes prior to the infusion):

• Dexamethasone 40 mg orally or IV (or 20 mg orally or IV for patients 75 years or older).
• Acetaminophen 650 mg to 1000 mg orally (or equivalent).
• H2 antagonists.
• Diphenhydramine 25 to 50 mg orally or IV (or equivalent). The IV route is preferred for at least the first 4 infusions.
• In combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor.

Geriatric Dose for Multiple Myeloma

IN COMBINATION WITH POMALIDOMIDE AND DEXAMETHASONE:

• Cycle 1: 10 mg/kg IV on Days 1, 8, 15, and 22 (weekly)
• Cycle 2 and beyond: 10 mg/kg IV on Days 1 and 15 (every 2 weeks)
• Each treatment cycle consists of a 28-day period.
• Therapy is repeated until disease progresses or unacceptable toxicity.

Recommended Premedications (administer 15 to 60 minutes prior to the infusion):

• Dexamethasone 40 mg orally or IV (or 20 mg orally or IV for patients 75 years or older).
• Acetaminophen 650 mg to 1000 mg orally (or equivalent).
• H2 antagonists.
• Diphenhydramine 25 to 50 mg orally or IV (or equivalent). The IV route is preferred for at least the first 4 infusions.
• In combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor

Dose Adjustments

• No dose reductions are recommended. A dose delay may be required to allow recovery of blood counts in the event of hematological toxicity.
• For information concerning drugs given in combination with this drug, see the manufacturer’s prescribing information.

Administration advice:

• This drug should be administered by a healthcare professional, with access to emergency? equipment and medical support to manage possible infusion-related reactions.
• If a dose is missed, administer it as soon as possible and adjust the schedule accordingly, maintaining the treatment interval.
• Administer the solution 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).
• The infusion solution should be administered for a period that will depend on the infusion rate.
• Use the prepared solution within 48 hours when stored refrigerated at 2C to 8C, followed by 8 hours (including the infusion time) at room temperature.
• Do not administer this drug concomitantly in the same IV line with other agents.
• Discard unused portions of the solution.
• Inspect the product visually for particulate matter and discoloration prior to administration.
• The manufacturer’s product information should be consulted for reconstitution recommendations.
• The infusion bag should be made of polyolefins (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) with di-(2-Ethylhexyl) phthalate (DEHP) or ethyl vinyl acetate (EVA).
• Gently homogenize the diluted solution by inverting the bag. Do not shake.

Side Effects

The Most Common

• diarrhea?
• nausea
• vomiting?
• chills, sore throat?, fever?, or cough; pain? or burning upon urination; or other signs of infection?
• unusual bleeding, easy bruising?, or red blood in stools
• shortness of breath?, dizziness? or weakness?, or pale skin
• difficulty breathing, cough, or swelling? of the leg(s)

More common

• Back pain
• black, tarry stools
• bleeding gums
• blood in the urine or stools
• blurred vision
• body aches or pain
• chest pain or tightness
• chills
• cough
• difficulty in breathing
• dizziness
• ear congestion
• enlarged pupils
• feeling of warmth
• fever
• flushing
• headache
• hoarseness
• increased sensitivity of the eyes to light
• increased sweating, possibly with fever or cold, clammy skin
• loss of voice
• lower back or side pain
• nausea
• nervousness
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• pounding in the ears
• redness of the face, neck, arms, and occasionally, upper chest
• runny or stuffy nose
• slow or fast heartbeat
• sneezing
• sore throat
• stiff or sore neck
• trouble breathing
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting
• Diarrhea
• trouble sleeping

Rare

• easy bruising, unusual bleeding, purple or red spots under your skin;
• low white blood cell counts–fever, mouth sores, skin sores, sore throat, cough, trouble breathing;
• low red blood cells (anemia)–pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet; or
• symptoms of pneumonia–cough with mucus, chest pain, feeling short of breath.
• low blood cell counts;
• pneumonia;
• diarrhea; or
• cold symptoms such as stuffy nose, sneezing, sore throat;
• increased sensitivity of the eyes to light
• increased sweating, possibly with fever or cold, clammy skin
• loss of voice
• lower back or side pain
• nausea
• nervousness
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• pounding in the ears
• redness of the face, neck, arms, and occasionally, upper chest
• runny or stuffy nose
• slow or fast heartbeat
• sneezing
• sore throat
• stiff or sore neck
• trouble breathing
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness

Drug Interactions

Pregnancy and Lactation

FDA Pregnancy Category C

Pregnancy

SARCLISA can cause fetal harm when administered to a pregnant woman. The assessment of rituximab-erfc-associated risks is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data). There are no available data on SARCLISA use in
pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction toxicity studies have not been conducted with isatuximab-irfc. The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, miscarriages, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2% to 4% and 15% to 20%, respectively. The combination of SARCLISA and pomalidomide is contraindicated in pregnant women because pomalidomide may cause birth defects and the death of the unborn child. Refer to the pomalidomide prescribing information on use during pregnancy. Pomalidomide is only available through a REMS program.

Lactation

There are no available data on the presence of isatuximab-irfc in human milk, milk production, or the effects on the breastfed child. Maternal immunoglobulin G is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the
breastfed infant to SARCLISA are unknown. Because of the potential for serious adverse reactions in the breastfed child from isatuximab-irfc administered in combination with pomalidomide and dexamethasone, advise lactating women not to breastfeed during treatment with SARCLISA. Refer to pomalidomide prescribing information for additional information.