Isatuximab is a CD-38 directed cytolytic antibody indicated for the treatment of relapsed or refractory multiple myeloma in combination with pomalidomide and dexamethasone in patients who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor and in combination with carfilzomib and dexamethasone in patients who have received 1 to 3 prior lines of therapy. Because isatuximab binds to CD38 on red blood cells, it may interfere with the ability to determine a patient's blood type and result in a false positive indirect antiglobulin test (Coombs test). Additionally, isatuximab may interfere with the determination of complete response in some patients. Patients should have their blood typed and screened prior to starting treatment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Premedication with acetaminophen PO, diphenhydramine IV or PO, a H2 antagonist, and dexamethasone IV or PO is required prior to each infusion; hold therapy for infusion-related reactions.
-If a dose is missed, administer isatuximab as soon as possible and adjust the dosing schedule to maintain the treatment interval.
-Initial infusion rates differ for first, second, and subsequent infusions; the maximum infusion rate is 200 mL/hour.
Dilution:
-Withdraw the appropriate amount (mL) from the isatuximab 20 mg/mL vials for the calculated dose (use actual body weight).
-From a 250-mL 0.9% Sodium Chloride injection or 5% Dextrose injection bag, remove a quantity (mL) of diluent equal to the amount of drug that will be injected. Inject the calculated dose of isatuximab into the infusion bag.
-Gently invert the bag to mix the solution but do not shake.
-Infusion bags/containers must be made of polyolefins, polyethylene (PE), polypropylene, polyvinyl chloride (PVC) with di-(2-ethylhexyl) phthalate (DEHP) or ethyl vinyl acetate.
-Storage of admixture: use within 48 hours when stored refrigerated (2 to 8 degrees C or 36 to 46 degrees F) followed by 8 hours (including the infusion time) at room temperature.
Intravenous Infusion:
-Administer isatuximab using an IV tubing infusion set (in PE, PVC with or without DEHP, polybutadiene, or polyurethane) with a 0.22 micron in-line filter (polyethersulfone, polysulfone, or nylon).
-Do not infuse isatuximab concomitantly with other drugs in the same IV line.
-Administer the diluted admixture as an IV infusion at the appropriate infusion rate as follows:
First infusion: start at 25 mL/hour; if there is no infusion-related reaction after 60 minutes, increase the infusion rate by 25 mL/hour every 30 minutes to a maximum rate of 150 mL/hour.
Second infusion: start at 50 mL/hour; if there is no infusion-related reaction after 30 minutes, increase the infusion rate by 50 mL/hour for 30 minutes and then by 100 mL/hour to a maximum rate of 200 mL/hour.
Subsequent infusions: start at 200 mL/hour.
Dyspnea (17% vs. 12%; grade 3, 5% vs. 1.3%) occurred more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus pomalidomide and dexamethasone (n = 152) compared with pomalidomide and dexamethasone alone (n = 149) in a randomized trial. Additionally, dyspnea (29% vs. 24%; grade 3, 5% vs. 0.8%) and cough (23% vs. 15%) were reported more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus carfilzomib and dexamethasone (n = 177) compared with carfilzomib and dexamethasone alone (n = 122) in another randomized trial.
Diarrhea (26% vs. 19%; grade 3, 2% vs. 0.7%), nausea (15% vs. 9%), and vomiting (12% vs. 3.4%; grade 3, 1.3% vs. 0%) occurred more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus pomalidomide and dexamethasone (n = 152) compared with pomalidomide and dexamethasone alone (n = 149) in a randomized trial. Additionally, diarrhea (36% vs. 29%; grade 3, 2.8% vs. 2.5%) and vomiting (15% vs. 9%; grade 3, 1.1% vs. 0.8%) were reported more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus carfilzomib and dexamethasone (n = 177) compared with carfilzomib and dexamethasone alone (n = 122) in another randomized trial.
Severe myelosuppression has been reported in patients who received isatuximab-containing regimens for the treatment of multiple myeloma in clinical studies. Obtain complete blood counts periodically during therapy. In patients who develop grade 4 neutropenia, hold the isatuximab dose until the neutrophil count recovers to at least 1 X 109 cells/L. An isatuximab dose reduction is not recommended. Monitor patients who develop neutropenia for signs and symptoms of infectious adverse events; provide supportive care with growth factors per institutional guidelines. Hematologic adverse events that were reported more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus pomalidomide and dexamethasone (n = 152) compared with pomalidomide and dexamethasone alone (n = 149) in a randomized trial included anemia (99% vs. 97%; grade 3, 32% vs. 28%), neutropenia (96% vs. 92%; grade 3, 24% and 38%; grade 4, 61% vs. 31%), lymphopenia (92% and 92%; grade 3, 42% vs. 35%; grade 4, 13% vs. 8%), and thrombocytopenia (84% vs. 79%; grade 3, 14% vs. 9%; grade 4, 16% vs. 15%). Additionally, hematologic adverse events that were reported more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus carfilzomib and dexamethasone (n = 177) compared with carfilzomib and dexamethasone alone (n = 149) in another randomized trial included anemia (99% and 99%; grade 3, 22% vs. 20%), neutropenia (55% vs. 43%; grade 3, 18% and 7%; grade 4, 1.7% vs. 0.8%), lymphopenia (94% and 95%; grade 3, 52% vs. 43%; grade 4, 17% vs. 14%), and thrombocytopenia (94% vs. 88%; grade 3, 19% vs. 16%; grade 4, 11% vs. 8%).
Grade 3 or higher infections have been reported in 38% and 43% of patients who received isatuximab-containing regimens for the treatment of multiple myeloma in 2 clinical trials. Consider administering prophylactic antibiotics during treatment; start antiviral prophylaxis per standard guidelines to prevent herpes zoster reactivation. Pneumonia (31% vs. 23%; grade 3, 22% vs. 16%; grade 4, 3.3% vs. 2.7%), upper respiratory tract infection (57% vs. 42%; grade 3, 9% vs. 3.4%), herpes zoster (4.6% vs. 0.7%), and febrile neutropenia (12% vs. 2%; grade 3, 11% vs. 1.3%; grade 4, 1.3% vs. 0.7%) occurred more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus pomalidomide and dexamethasone (Isa-Pd arm; n = 152) compared with pomalidomide and dexamethasone alone (n = 149) in a randomized trial. Additionally, fatal infections were reported in 3.3% of patients who received Isa-Pd. Pneumonia (36% vs. 30%; grade 3, 19% vs. 15%; grade 4, 3.4% vs. 2.5%), upper respiratory tract infection (67% vs. 57%; grade 3, 9% vs. 7%), bronchitis (24% vs. 13%; grade 3, 2.3% vs. 0.8%), and herpes zoster (2.3% vs. 1.6%) were reported more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus carfilzomib and dexamethasone (Isa-Kd arm; n = 177) compared with carfilzomib and dexamethasone alone (n = 122) in another randomized trial. Febrile neutropenia (1.1%) and fatal infections (2.3%) including from pneumonia (1.7%) were also reported in patients who received Isa-Kd. Neutropenic complications including neutropenic infections (defined as infection with concurrent grade 3 or higher neutropenia) were reported in 30% of patients treated with Isa-Pd and 2.8% of patients treated with Isa-Kd. The most common neutropenic infections in patients who received Isa-Pd included upper respiratory tract infection (10%), lower respiratory tract infection (9%), and urinary tract infection (3%). The term upper respiratory tract infection included bronchiolitis, bronchitis, sinusitis, pharyngitis/nasopharyngitis, influenza-like illness, laryngitis, parainfluenza virus infection, tracheitis, nasal herpes, respiratory syncytial virus infection, rhinitis, and tonsillitis.
New primary malignancy was reported in 4.1% of patients who received isatuximab therapy. Monitor patients for the development of new primary malignancies. New primary malignancies (7% vs. 2%) occurred more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus pomalidomide and dexamethasone (n = 152) compared with pomalidomide and dexamethasone alone (n = 149) in a randomized trial. Additionally, new primary malignancies (7% vs. 4.9%) were reported more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus carfilzomib and dexamethasone (n = 177) compared with carfilzomib and dexamethasone alone (n = 122) in another randomized trial. In these clinical trials (n = 329), the most common new primary malignancies were skin cancer (5%) and noncutaneous solid tumors (3%). Isatuximab therapy was continued after resection in all patients who developed skin cancer.
Hypertension (37% vs. 32%; grade 3, 20% vs. 18%; grade 4, 0.6% and 1.6%) including hypertensive crisis occurred more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus carfilzomib and dexamethasone (n = 177) compared with carfilzomib and dexamethasone alone (n = 122) in a randomized trial.
Infusion-related reactions have been reported in patients who received isatuximab therapy; anaphylactoid reactions occurred in less than 1% of patients. Most reactions start during the first infusion or first treatment cycle and resolve on the same day. Monitor vital signs frequently during the isatuximab infusion for signs and symptoms of infusion-related reactions. Common symptoms include dyspnea, cough, chills, nasal congestion, and nausea; serious and life-threatening reactions include cardiac arrest, hypertension, hypotension, bronchospasm, dyspnea, angioedema, and swelling. Stop the infusion and initiate appropriate medical support if a grade 2 or higher infusion-related reaction occurs; an infusion rate reduction or permanent discontinuation may be necessary depending on the severity of the reaction. Premedication with acetaminophen PO, diphenhydramine IV or PO, a H2 antagonist, and dexamethasone IV or PO is required prior to each infusion. Infusion-related reactions (38%; grade 3, 1.3%; grade 4, 1.3%) occurred in patients with relapsed or refractory multiple myeloma who received isatuximab plus pomalidomide and dexamethasone (n = 152) in a randomized trial; no patients in the pomalidomide and dexamethasone alone arm (n = 149) had an infusion reaction. Additionally, infusion-related reactions (46% vs. 3.3%; grade 3, 0.6% vs. 0%) occurred more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus carfilzomib and dexamethasone (n = 177) compared with carfilzomib and dexamethasone alone (n = 122) in another randomized trial. The term infusion-related reactions included cytokine release syndrome and hypersensitivity.
Antibody formation occurred in 1.9% of multiple myeloma patients who received isatuximab as a single agent or in combination with other therapies (n = 1,018).
Heart failure, including congestive heart failure, left ventricular failure, and pulmonary edema, occurred in 7% of patients with relapsed or refractory multiple myeloma who received isatuximab plus carfilzomib and dexamethasone (Isa-Kd arm; n = 177) or carfilzomib and dexamethasone alone (Kd arm; n = 122) in a randomized trial. Grade 3 or higher heart failure was reported in 4% and 4.1% of patients in the Isa-Kd and Kd arms, respectively. Fatal heart failure was reported in 1.1% of patients who received Isa-Kd in this trial.
Fatigue (42% vs. 32%; grade 3, 5% vs. 3.3%) including asthenia occurred more often in patients with relapsed or refractory multiple myeloma who received isatuximab plus carfilzomib and dexamethasone (n = 177) compared with carfilzomib and dexamethasone alone (n = 122) in a randomized trial.
Infusion-related reactions (e.g., cough, chills, and nausea) have been reported with isatuximab therapy; most reactions start during the first infusion or first treatment cycle and resolve on the same day. Serious and life-threatening reactions may include cardiac arrest, hypertension, hypotension, bronchospasm, dyspnea, angioedema, swelling, or anaphylaxis. Use is contraindicated in patients who have a history of a severe hypersensitivity reaction with isatuximab or any other component of the product. Monitor vital signs frequently during the isatuximab infusion and for signs and symptoms of infusion-related reactions. Stop the infusion and initiate appropriate medical support if a grade 2 or higher infusion-related reaction occurs; an infusion rate reduction or permanent discontinuation may be necessary depending on the severity of the reaction. Premedication with acetaminophen, diphenhydramine, a H2 antagonist, and dexamethasone is required prior to each infusion.
New primary malignancy (e.g., skin cancer) has been reported in patients who received isatuximab-containing regimens for the treatment of multiple myeloma. Monitor patients for the development of new primary malignancies.
Laboratory test interference has been reported with isatuximab therapy. Isatuximab binds to CD38 on red blood cells (RBCs) and may interfere with blood bank serologic tests and result in false positive reactions in indirect antiglobulin tests (indirect Coombs test), antibody detection (screening) tests, antibody identification panels, and antihuman globulin crossmatches. A false positive indirect Coombs test was observed in 63% and 68% of tested patients following isatuximab-containing therapy in clinical trials. Patients should have their blood typed and screened prior to starting treatment and consider phenotyping. In the event of a planned blood transfusion, inform personnel at blood transfusion centers that the patient is receiving isatuximab; interference with blood compatibility testing can be resolved using dithiothreitol-treated RBCs. If a patient requires an emergency transfusion, non-cross-matched ABO/RhD-compatible RBCs can be given as local blood bank practice dictates. Determination of ABO and Rh blood type are not affected by isatuximab. Additionally, isatuximab can be detected on both the serum protein electrophoresis and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein which may interfere with the determination of complete response (CR) based on International Myeloma Working Group (IMWG) criteria. Consider using a FDA-approved isatuximab-specific IFE assay to determine a CR in patients with persistent very good partial response in which test interference is suspected.
Neutropenia and neutropenic complications (e.g., febrile neutropenia, neutropenic infection) have been reported in patients who received isatuximab-containing regimens for the treatment of multiple myeloma. Monitor complete blood counts periodically during therapy. In patients who develop grade 4 neutropenia, hold the isatuximab dose until the neutrophil count recovers to at least 1 X 109 cells/L. An isatuximab dose reduction is not recommended. Monitor patients who develop neutropenia for signs and symptoms of infection; provide supportive care with growth factors per institutional guidelines. Consider administering prophylactic antibiotics during treatment; start antiviral prophylaxis per standard guidelines to prevent herpes zoster reactivation.
Isatuximab may cause fetal harm if administered during pregnancy, based on its mechanism of action. Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta; therefore, it is possible that isatuximab may cause fetal CD38-cell depletion and decreased bone density. Prior to administering a live vaccination, evaluate hematologic parameters in neonates and infants whose mother received isatuximab during pregnancy. Isatuximab is used in combination with pomalidomide which is contraindicated in pregnant women because pomalidomide may cause birth defects and death of the unborn child.
Counsel patients about the reproductive risk and contraception requirements during isatuximab treatment. Females of reproductive potential should receive pregnancy testing prior to starting isatuximab. These patients should avoid pregnancy and use effective contraception during and for 5 months after treatment with isatuximab. Women who become pregnant while receiving isatuximab should be apprised of the potential hazard to the fetus.
It is not known if isatuximab is secreted in human milk or if it has effects on the breast-fed child or on milk production. Maternal IgG is present in human milk; however, the effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to isatuximab are unknown. Because of a potential for serious adverse reactions in nursing infants from isatuximab used in combination with pomalidomide and dexamethasone, women should discontinue breast-feeding during isatuximab therapy.
For the treatment of multiple myeloma:
NOTE: The FDA has designated isatuximab as an orphan drug for the treatment of multiple myeloma.
-for the treatment of multiple myeloma in patients who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor, in combination with pomalidomide and dexamethasone:
Intravenous dosage:
Adults: 10 mg/kg (actual body weight) IV on days 1, 8, 15, and 22 on cycle 1 and 10 mg/kg (actual body weight) IV on days 1 and 15 starting on cycle 2; give isatuximab in combination with pomalidomide 4 mg orally daily on days 1 to 21 and dexamethasone 40 mg (or 20 mg in patients 75 years and older) IV or orally on days 1, 8, 15, and 22. Repeat treatment cycles every 28 days until disease progression. Measure weight prior to each cycle and adjust the isatuximab dose accordingly. Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 15 to 60 minutes prior to isatuximab: acetaminophen 650 to 1,000 mg orally (or equivalent), diphenhydramine 25 to 50 mg (or equivalent) IV (preferred for the first 4 infusions) or orally, and a H2 antagonist. Also premedicate with dexamethasone 40 mg (or 20 mg in patients 75 years and older) IV or orally prior to the isatuximab infusion and pomalidomide dose as part of the scheduled regimen dose. Consider administering prophylactic antibiotics during treatment; start antiviral prophylaxis per standard guidelines to prevent herpes zoster reactivation. At a median follow-up time of 11.6 months, the median progression-free survival time (evaluated by an independent response committee) was significantly improved in patients with relapsed or refractory multiple myeloma who received isatuximab, pomalidomide, and low-dose dexamethasone compared with pomalidomide and low-dose dexamethasone alone (11.5 months vs. 6.5 months; hazard ratio (HR) = 0.596; 95% CI, 0.44 to 0.81; p = 0.001) in a multinational, randomized, phase 3 trial (the ICARIA-MM trial; n = 307). Patients (median age, 67 years) in this study had received a median of 3 prior therapies including lenalidomide and a proteasome inhibitor; 56% of patients had previously received an autologous stem-cell transplantation. At a second interim analysis (median follow-up, 35.3 months), the median overall survival time was 24.6 months in patients who received isatuximab, pomalidomide, and dexamethasone compared with 17.7 months in patients who received pomalidomide and dexamethasone (HR = 0.76; 95% CI, 0.57 to 1.01). Subsequent therapy was given at disease progression in 60% and 72% of patients in the isatuximab-containing and control arms, respectively. Of patients who received subsequent therapy, fewer patients received daratumumab in the isatuximab-containing arm (24% vs. 58%).
-for the treatment of relapsed or refractory multiple myeloma in patients who have received 1 to 3 prior lines of therapy, in combination with carfilzomib and dexamethasone:
Intravenous dosage:
Adults: 10 mg/kg (actual body weight) IV on days 1, 8, 15, and 22 on cycle 1 and 10 mg/kg (actual body weight) IV on days 1 and 15 starting on cycle 2; give isatuximab in combination with carfilzomib (cycle 1: 20 mg/m2 on days 1 and 2 and then 56 mg/m2 on days 8, 9, 15, and 16; cycle 2 and beyond: 56 mg/m2 on days 1, 2, 8, 9, 15, and 16) and dexamethasone (20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23). Repeat treatment cycles every 28 days until disease progression. When isatuximab and carfilzomib are given on the same day, give dexamethasone IV first, then isatuximab, and carfilzomib last. Measure weight prior to each cycle and adjust the isatuximab dose accordingly. Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 15 to 60 minutes prior to isatuximab: acetaminophen 650 to 1,000 mg orally (or equivalent), diphenhydramine 25 to 50 mg (or equivalent) IV (preferred for the first 4 infusions) or orally, and a H2 antagonist. Give IV dexamethasone prior to isatuximab and/or carfilzomib on days these agents are given on the same day and then give dexamethasone orally for other scheduled doses. Consider administering prophylactic antibiotics during treatment; start antiviral prophylaxis per standard guidelines to prevent herpes zoster reactivation. At a median follow-up time of 44 months, the median progression-free survival time (evaluated by an independent review committee) was significantly improved in patients with relapsed or refractory multiple myeloma who received isatuximab, carfilzomib, and dexamethasone compared with carfilzomib and dexamethasone alone (35.7 months vs. 19.2 months; hazard ratio (HR) = 0.58; 95% CI, 0.42 to 0.79) in a prespecified interim analysis of a multinational, randomized, phase 3 trial (the IKEMA trial; n = 302). Median overall survival (OS) was not significantly improved in isatuximab-treated patients (HR = 0.78; 95% CI, 0.54 to 1.12); however, OS data were not mature at this analysis. Patients (median age, 65 years) in the isatuximab-treated arm had received a median of 2 (range, 1 to 4) prior therapies and 49.7% of patients were refractory to the last regimen.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Infusion-Related Reactions
Grade 2 or 3 toxicity: Stop the infusion. If symptoms improve to grade 1 or less, resume the infusion at half of the initial infusion rate; provide supportive care as necessary and monitor patients closely. If symptoms do not recur after 30 minutes, increase the rate to the initial infusion rate. The infusion rate may then be titrated up at the schedule and rate increment used for the first, second, and subsequent infusions. If symptoms do not improve to grade 1 or less or persist or worsen, or if hospitalization is required, permanently discontinue isatuximab therapy.
Grade 4 toxicity including anaphylaxis: Permanently discontinue isatuximab therapy; provide appropriate medical support.
Hematologic Toxicity
Grade 4 neutropenia: Hold the isatuximab dose until the neutrophil count recovers to at least 1 X 109 cells/L. Use growth factor support per institutional guidelines.
Maximum Dosage Limits:
-Adults
10 mg/kg (actual body weight) IV weekly.
-Geriatric
10 mg/kg (actual body weight) IV weekly.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
-Infants
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
No isatuximab dosage adjustment is necessary in patients with pre-existing mild (total bilirubin level of 1 to 1.5 times the upper limit of normal (ULN) or AST level greater than the ULN) hepatic impairment based on a population pharmacokinetic analysis. Isatuximab has not been evaluated in patients with moderate (total bilirubin level 1.5 to 3 times the ULN and any AST level) or severe (total bilirubin level greater than 3 times the ULN and any AST level) hepatic impairment.
Patients with Renal Impairment Dosing
No isatuximab dosage adjustment is necessary in patients with pre-existing renal impairment based on a population pharmacokinetic analysis.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Isatuximab is an IgG1-derived monoclonal antibody that binds to CD38 expressed on the surface of normal and multiple myeloma tumor cells. It inhibits the ADP-ribosyl cyclase activity of CD38, activates natural killer cells in the absence of CD38-positive target tumor cells, and suppresses CD38-positive T-regulatory cells. CD38-directed antibodies cause tumor cell death via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, and apoptosis. Isatuximab differs from another CD38-directed monoclonal antibody, daratumumab, in its ability to induce direct apoptosis without cross-linking and its dose-dependent inhibition of CD38 enzymatic activity in vitro. Isatuximab has demonstrated synergistic activity with immunomodulatory agents such as lenalidomide and pomalidomide in phase 1b dose escalation trials.
Isatuximab is administered as an IV infusion. Its mean predicted total volume of distribution is 8.13 L (coefficient of variation, 26.2%). Over 99% of the drug is eliminated from the plasma at approximately 2 months following the last isatuximab dose; elimination was similar when isatuximab was given as a single-agent or as part of combination therapy. Isatuximab total clearance decreased with increasing dose and repeated dosing. It is metabolized into small peptides by catabolic pathways.
-Route-Specific Pharmacokinetics
Intravenous Route
Following the administration of isatuximab in combination with pomalidomide and dexamethasone, the steady-state mean predicted Cmax level was 351 micrograms (mcg)/mL (coefficient of variation (CV), 36%) and the AUC value was 72,600 mcg x hour/mL (CV, 51.7%). Following the administration of isatuximab in combination with carfilzomib and dexamethasone, the steady-state mean predicted Cmax and AUC values were 655 mcg/mL (CV, 30.8%) and 159,000 mcg x hour/mL (CV, 37.1%), respectively. The median time to reach steady state was 18 weeks with 3.1-fold accumulation. Isatuximab AUC values increase proportionally over the dosage range of 5 to 20 mg/kg given weekly for 4 weeks followed by every 2-week dosing. Isatuximab AUC values increase more than dose proportionally over the dosage range of 1 to 20 mg/kg given every 2 weeks.
-Special Populations
Hepatic Impairment
Mild (total bilirubin level of 1 to 1.5 times the upper limit of normal (ULN) or AST level greater than the ULN) hepatic impairment had no clinically significant impact on the exposure of isatuximab. The effect of moderate (total bilirubin level 1.5 to 3 times the ULN and any AST level) or severe (total bilirubin level greater than 3 times the ULN and any AST level) hepatic impairment on the pharmacokinetics of isatuximab is not known.
Renal Impairment
Renal impairment (estimate glomerular filtration rate less than 90 mL/min/1.73 m2) had no clinically significant impact on the exposure of isatuximab.
Geriatric
Age (range, 36 to 85 years) has no clinically significant impact on the exposure of isatuximab.
Gender Differences
Gender has no clinically significant impact on the exposure of isatuximab.
Ethnic Differences
White (n = 377; 79%) and Asian (n = 25; 5%) race has no clinically significant impact on the exposure of isatuximab. The effect of Black race (n = 18; 4%) on isatuximab exposure is not known.
Obesity
The clearance of isatuximab increases with increasing body weight.