Isatuximab, a chimeric anti-CD38 monoclonal antibody, is an antineoplastic agent.1, 2, 3
Isatuximab-irfc is used in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma in adults who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor.1 Isatuximab-irfc is also used in combination with carfilzomib and dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.1 Isatuximab-irfc is also used in combination with bortezomib, lenalidomide, and dexamethasone for the treatment of adults with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant (ASCT).1 Isatuximab has been designated an orphan drug by FDA for use in multiple myeloma.4
Combination Therapy with Pomalidomide and Dexamethasone
The indication for isatuximab-irfc in combination with pomalidomide and dexamethasone is based principally on the results of a randomized, open-label, phase 3 study (ICARIA-MM) in 307 patients with relapsed or refractory multiple myeloma previously treated with at least 2 prior therapies including lenalidomide and a proteasome inhibitor.1, 3, 5 Exclusion criteria included prior therapy with pomalidomide.3, 5 In this study, patients were randomized to receive isatuximab-irfc 10 mg/kg administered by IV infusion once weekly for 4 doses during cycle 1, followed by every 2 weeks of each 28-day cycle thereafter.1, 3, 5 All patients received pomalidomide (4 mg orally once daily on days 1-21 of each 28-day cycle) and dexamethasone (20-40 mg orally or IV on days 1, 8, 15, and 22 of each 28-day cycle).1, 3, 5 Treatment was continued until disease progression or unacceptable toxicity occurred.1, 3, 5 The primary measure of efficacy was progression-free survival (as assessed by an independent review committee) using the International Myeloma Working Group (IMWG) criteria.1, 3, 5 The median age of the patient population was 67 years and patients received a median of 3 prior therapies for treatment of myeloma; 56% previously underwent stem cell transplantation, and 37, 36, or 25% of patients were at stage I, II, or III disease, respectively, at study entry.1, 3, 5 High-risk cytogenetic features (i.e., del(17p), t(4;14) and/or t(14;16) chromosomal abnormality) were present in 20% of patients at study entry.1, 3, 5 All patients in the study received prior therapy with a proteasome inhibitor or lenalidomide; 93, 76, or 73% of patients were refractory to lenalidomide, a proteasome inhibitor, or an immunomodulator and a proteasome inhibitor, respectively.1, 3, 5
At a median follow-up of 11.6 months, progression-free survival was substantially longer in patients receiving isatuximab-irfc in combination with pomalidomide and dexamethasone compared with those receiving pomalidomide and dexamethasone alone (11.5 versus 6.5 months).1, 3, 5 Patients receiving the isatuximab-irfc combination regimen also had higher overall response rates compared with those receiving pomalidomide and dexamethasone alone (60 versus 35%); stringent complete response and complete responses were achieved in 5 or 2% of patients receiving these respective treatments.1, 3, 5 The median time to initial response was 35 or 58 days in patients receiving the isatuximab-irfc combination regimen or pomalidomide in combination with dexamethasone alone, respectively; the median duration of response was 13.3 or 11.1 months in patients receiving these respective treatments.1, 3, 5 Median overall survival had not been reached in either group at the time of the efficacy analysis; however, overall survival was 72% in patients receiving the isatuximab-irfc combination regimen and 63% in those receiving pomalidomide and dexamethasone alone.3, 5 Results of a subgroup analysis (based on age, baseline renal function, number of prior therapies, prior autologous stem cell transplantation, cytogenetic risk, disease stage, refractoriness to lenalidomide and/or proteasome inhibitors) suggested that the effect of isatuximab-irfc combination therapy on progression-free survival was consistent across all subgroups.3, 5 Prespecified subgroup analysis also suggested that complete renal response (defined as an improvement in estimated glomerular filtration rate [eGFR] from less than 50 mL/min per 1.73 m2 at baseline to 60 mL/minute or greater on at least one post-baseline assessment) was improved in patients receiving isatuximab-irfc in combination with pomalidomide and dexamethasone compared with those receiving pomalidomide and dexamethasone alone.3, 14 In an updated analysis at a median follow-up of 52.4 months, final median overall survival was 24.6 months in the isatuximab-irfc combination group and 17.7 months in the group receiving pomalidomide and dexamethasone alone.1
Combination with Carfilzomib and Dexamethasone
The indication for isatuximab-irfc in combination with carfilzomib and dexamethasone is based principally on the results of an open-label, multicenter, randomized, phase 3 trial (IKEMA).1, 16 In this trial, 302 adults with relapsed or refractory multiple myeloma were randomized to receive isatuximab-irfc in combination with carfilzomib and dexamethasone or carfilzomib and dexamethasone alone in 28-day cycles until disease progression or unacceptable toxicity.1, 16 Isatuximab-irfc was administered at a dosage of 10 mg/kg as a weekly IV infusion in the first cycle and then every 2 weeks thereafter.1, 16 Carfilzomib was administered as an IV infusion at a dose of 20 mg/m2 on days 1 and 2 of cycle 1; a dose of 56 mg/m2 on days 8, 9, 15, and 16 of cycle 1; and a dose of 56 mg/m2 on days 1, 2, 8, 9, 15, and 16 for each cycle thereafter.1, 16 Oral or IV dexamethasone was administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle.1, 16 The median age of patients in the study was 64 years; 56% were male, 71% were white, 17% were Asian, and 3% were Black.1, 16 Patients received a median of 2 prior lines of therapy before study enrollment and 44% of patients received 1 prior line of therapy.1 In the overall population of patients in the IKEMA trial, 90% of patients received prior proteasome inhibitors, 78% received prior immunomodulators, and 61% received prior stem cell transplantation.1 The main efficacy outcome was progression-free survival as assessed by an Independent Response Committee using the International Myeloma Working Group (IMWG) criteria.1 Patients who received isatuximab-irfc in combination with carfilzomib and dexamethasone had prolonged progression-free survival compared with those who received carfilzomib and dexamethasone alone.1 At a median follow-up of 20.7 months, median progression-free survival was not reached for patients in the isatuximab-irfc, carfilzomib, and dexamethasone group compared with 19.5 months for patients in the carfilzomib and dexamethasone group.1 Final analysis of progression-free survival at a median follow-up of 44 months showed a median progression-free survival of 41.7 months in patients treated with isatuximab-irfc, carfilzomib, and dexamethasone compared with 20.8 months for those treated with carfilzomib and dexamethasone alone; final complete response rate was 44% and 28.5% in these respective treatment groups.1 At a median follow-up of 57 months, median overall survival was not reached in the isatuximab-irfc combination group and was 50.6 months in the control group.1
Combination with Bortezomib, Lenalidomide, and Dexamethasone
The indication for isatuximab-irfc in combination with bortezomib, lenalidomide, and dexamethasone is based principally on the results of a multicenter, open-label, randomized, phase 3 trial (IMROZ).1, 17 A total of 446 adults with previously untreated myeloma and symptomatic measurable disease who were ineligible to undergo transplantation were randomized to receive isatuximab-irfc in combination with subcutaneous bortezomib, oral lenalidomide, and dexamethasone (IV or oral) or the combination of bortezomib, lenalidomide, and dexamethasone alone.1, 17 All patients received 4 induction cycles with 6 weeks per cycle, followed by 4-week cycles of continuous treatment until disease progression or unacceptable toxicity.1, 17 During the induction period, isatuximab-irfc was administered at a dose of 10 mg/kg as an IV infusion on days 1, 8, 15, 22, and 29 in the first cycle and then on days 1, 15, and 29 from cycles 2 to 4.1 Bortezomib was administered subcutaneously at a dose of 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of each cycle.1, 17 Oral lenalidomide was administered at a dose of 25 mg once daily from days 1 to 14 and from days 22 to 35 of each cycle, and IV or oral dexamethasone was administered at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each cycle.1 During the continuous treatment period (from cycle 5 onwards), isatuximab-irfc was administered at a dose of 10 mg/kg as an IV infusion on days 1 and 15 from cycles 5 to 17, followed by monthly administration thereafter starting with cycle 18.1, 17 Lenalidomide was administered orally at a dose of 25 mg once daily from days 1 to 21 of each cycle, and IV or oral dexamethasone was administered at a dose of 20 mg on days 1, 8, 15, and 22 of each cycle.1, 17
The median age of patients enrolled in the IMROZ study was 72 years; 72% of the patients were white, 11% were Asian, and 0.9% were Black.1, 17 Approximately 17% of the patients had high-risk cytogenetic features at study entry.1, 17 The main efficacy endpoint was progression-free survival as assessed by an Independent Response Committee using the IMWG criteria.1 At a median follow-up of 60 months, the median progression-free survival had not been reached for patients who received isatuximab-irfc in combination with bortezomib, lenalidomide, and dexamethasone and was 54.3 months for patients who received the combination of bortezomib, lenalidomide, and dexamethasone alone.1, 17 Median overall survival had not been reached for either group at 60 months; as of this data-cutoff date, 26% and 32.6% of patients in the isatuximab-irfc combination group and control group, respectively, had died; estimated overall survival rates were 72.3% and 66.3%, respectively.17
In 2019, the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) published evidence-based recommendations for the treatment of multiple myeloma, including recommendations for patients who are autologous stem cell transplant eligible, patients who are transplant ineligible, and patients with relapsed or refractory disease.38 For transplant eligible patients, the guideline states that at least 3-4 cycles of induction therapy, including an immunomodulatory drug (e.g., thalidomide, lenalidomide), a proteasome inhibitor (e.g., bortezomib, carfilzomib), and steroids (e.g., dexamethasone), is advised prior to stem cell collection.38 ASCO and CCO state that consolidation therapy post-transplant is not routinely recommended but may be considered in the context of a clinical trial; at least 2 cycles may also be considered for patients ineligible or unwilling to consider maintenance therapy.38 For patients who are transplant ineligible, initial treatment should include, at minimum, an immunomodulatory drug or proteasome inhibitor and steroid if possible.38 Triplet therapies (e.g., bortezomib, lenalidomide, and dexamethasone) should be considered; daratumumab plus bortezomib, melphalan, and prednisone may also be considered.38 For the treatment of relapsed or refractory disease, the guideline recommends triplet therapy with 2 novel agents (i.e., an immunomodulatory drug, a proteasome inhibitor, or a monoclonal antibody) plus a corticosteroid.38 ASCO and CCO state that prior therapies should be taken into consideration when selecting the treatment at first relapse.38 Choice of therapy should be based on patient, disease, and treatment factors, including prior therapies.38
Updated information on the treatment of multiple myeloma is also available from the National Cancer Institute (NCI).39 These experts note that while there have been many new therapeutic agents over the past 20 years, there is currently no confirmed curative approach for the treatment of multiple myeloma.39 Patients who are newly diagnosed and require therapy are categorized as either "in good or well-controlled health (i.e., transplant eligible)" or as "less fit with significant comorbidities or advanced age (i.e., transplant ineligible)".39 For patients in "good or well-controlled health", triplet or quadruplet induction chemotherapy that includes bortezomib may be used in the absence of a clinical trial.39 NCI lists the following as commonly used regimens: daratumumab in combination with bortezomib, lenalidomide, and dexamethasone; bortezomib, lenalidomide, and dexamethasone; and cyclophosphamide, bortezomib, and dexamethasone.39 Patients responding to therapy after 4-8 months may then receive autologous stem cell transplant consolidation.39 Maintenance therapy is then given until disease relapse.39 For patients who are "less fit with significant comorbidities or advanced age", induction chemotherapy that includes a triplet or quadruplet regimen may be used.39 For better tolerability, a doublet regimen that includes either daratumumab or isatuximab may also be given.39 Therapy is continued until maximal response, and maintenance therapy is then administered until disease relapse.39 Options for maintenance therapy include lenalidomide, ixazomib, and daratumumab alone or in combination, as well as bortezomib.39 For patients who relapse after therapy, new combinations of drugs or single agents may be given sequentially as required.39 Monoclonal antibodies (e.g., daratumumab, elotuzumab, isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib), chimeric antigen receptor (CAR) T-cell therapy (e.g., ciltacabtagene autoleucel and idecabtagene vicleucel), bispecific antibody therapy (e.g., teclistamab, talquetamab, elranatamab), and immunomodulatory agents (e.g., pomalidomide, lenalidomide, thalidomide) are all treatment options for relapsed or refractory multiple myeloma.39 Additional treatment options for relapsed or refractory multiple myeloma include cytotoxic chemotherapy agents, selinexor, venetoclax, BRAF/MEK inhibitors, and corticosteroids.39
Dispensing and Administration Precautions
Isatuximab-irfc is administered by IV infusion.1 Isatuximab-irfc infusion solution should be administered with a polyurethane (PU), polybutadiene (PBD), polyvinyl chloride (PVC), or polyethylene (PE) infusion set equipped with a nylon, polysulfone, or polyethersulfone (PES) 0.22-µm inline filter.1
Isatuximab-irfc should not be administered simultaneously through the same IV line with other drugs.1
Unopened vials of isatuximab-irfc injection concentrate should be protected from light, stored at 2-8°C, and should not be frozen or shaken.1
If a dose is missed, the dose of isatuximab-irfc should be administered as soon as possible.1 The schedule of administration should be adjusted to maintain the appropriate treatment interval between doses.1
Prior to administration, commercially available isatuximab-irfc injection concentrate must be diluted using proper aseptic technique.1
Isatuximab-irfc injection concentrate should be inspected visually for particulate matter and discoloration; the injection concentrate should be clear to slightly opalescent and colorless to slightly yellow and essentially free of visible particulates.1
Isatuximab-irfc injection concentrate should be diluted in 0.9% sodium chloride injection or 5% dextrose injection to provide a total volume of 250 mL (i.e., if a 250-mL bag of 0.9% sodium chloride injection is used, a volume of the diluent equal to the total required volume of isatuximab-irfc injection concentrate should be removed from the infusion bag prior to addition of the injection concentrate).1 The total required volume of isatuximab-irfc injection concentrate should then be added to the diluent in a polyolefin, polypropylene, ethyl vinyl acetate, PVC with di-(2-ethylhexyl) phthalate (DEHP), or PE infusion bag.1
Diluted solutions of isatuximab-irfc should be mixed by gentle inversion and should not be shaken.1 The diluted solution for infusion may be stored at 2-8°C for up to 48 hours, followed by up to 8 hours at room temperature (including infusion time).1
Any unused portions of the injection concentrate or diluted solution should be discarded since the injection contains no preservative.1
The manufacturer states that an incremental escalation of the infusion rate as described in Table 1 may be considered in the absence of infusion-related reactions.1
Infusion | Initial Infusion Rate | Incremental Escalation of Infusion Rate |
|---|---|---|
First | 25 mL/hour | If infusion-related reactions do not occur after 60 minutes, increase infusion rate in increments of 25 mL/hour every 30 minutes to a maximum rate of 150 mL/hour |
Second | 50 mL/hour | If infusion-related reactions do not occur after 30 minutes, continue current infusion rate (50 mL/hour) for 30 minutes then increase in increments of 100 mL/hour to a maximum rate of 200 mL/hour |
Subsequent | 200 mL/hour | Do not exceed a maximum rate of 200 mL/hour |
For grade 2 or 3 infusion-related reactions, the infusion should be interrupted; once the reaction has improved to grade 0 or 1, the infusion may be resumed at a rate reduced by 50%.1 If infusion-related reactions do not recur after 30 minutes, the infusion rate may be increased to the initial rate, followed by an incremental escalation of the infusion rate (see Table 1).1 For grade 2 or 3 infusion-related reactions that do not improve following interruption of the infusion, persist or worsen despite appropriate symptomatic and supportive therapy, or require hospitalization, therapy with isatuximab-irfc should be permanently discontinued.1
If a grade 4 infusion-related reaction occurs, isatuximab-irfc should be permanently discontinued.1
The dosage of isatuximab-irfc should be calculated based on actual body weight prior to each dose.1
Clinicians should consult the respective manufacturers' labeling or published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens.1
Combination Therapy with Pomalidomide and Dexamethasone: For use in combination with pomalidomide and dexamethasone in the treatment of multiple myeloma in adults who have received at least 2 prior therapies, the recommend dosage of isatuximab-irfc is 10 mg/kg administered IV on days 1, 8, 15, and 22 during cycle 1 (28-day cycle).1 During subsequent cycles, the recommended dosage of isatuximab-irfc is 10 mg/kg administered IV on days 1 and 15.1 Treatment cycles are repeated every 28 days.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Combination Therapy with Carfilzomib and Dexamethasone: For use in combination with carfilzomib and dexamethasone in the treatment of relapsed or refractory multiple myeloma in adults who have received 1 to 3 prior lines of therapy, the recommend dosage of isatuximab-irfc is 10 mg/kg administered IV on days 1, 8, 15, and 22 during cycle 1 (28-day cycle).1 During subsequent cycles, the recommended dosage of isatuximab-irfc is 10 mg/kg administered IV on days 1 and 15.1 Treatment cycles are repeated every 28 days.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1 On the days where both isatuximab and carfilzomib are administered, administer dexamethasone first, followed by isatuximab and then carfilzomib.1
Combination Therapy with Bortezomib, Lenalidomide, and Dexamethasone: For use in combination with bortezomib, lenalidomide, and dexamethasone in the treatment of patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant (ASCT), the recommend dosage of isatuximab-irfc is 10 mg/kg administered IV on days 1, 8, 15, 22, and 29 during cycle 1 (42-day cycle).1 During cycles 2 to 4 (42-day cycles), the recommended dosage of isatuximab-irfc is 10 mg/kg administered IV on days 1, 15, and 29.1 During cycles 5 to 17 (28-day cycles), the recommended dosage of isatuximab-irfc is 10 mg/kg administered IV on days 1 and 15.1 During cycles 18 and beyond (28-day cycles), the recommended dosage of isatuximab-irfc is 10 mg/kg administered IV on day 1 of each cycle.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If adverse effects occur, the manufacturer does not recommend reducing the dosage of isatuximab-irfc.1
If grade 4 neutropenia occurs, isatuximab therapy should be interrupted until neutrophil counts recover to at least 1000/mm3.1 Use of growth factors to treat neutropenia should be administered as clinically indicated.1
If infusion-related reactions of grade 2 or greater severity occur, the infusion rate should be reduced or therapy should be permanently discontinued depending on the severity of the reaction, and appropriate symptomatic and supportive therapy should be provided.1
If a grade 4 infusion-related reaction occurs, isatuximab therapy should be permanently discontinued.1
No dosage adjustment is necessary in patients with mild hepatic impairment (total bilirubin concentrations exceeding the upper limit of normal [ULN], but no more than 1.5 times the ULN, or AST concentrations exceeding the ULN).1, 3
No dosage adjustment is necessary in patients with mild to severe renal impairment (estimated glomerular filtration rate [eGFR] less than 90 mL/minute per 1.73 m2).1, 3, 14
The manufacturer makes no specific dosage recommendations for geriatric patients.1
When isatuximab is used in combination with pomalidomide, carfilzomib, bortezomib, lenalidomide or dexamethasone, the usual cautions, precautions, and contraindications associated with these other drugs must be considered in addition to those associated with isatuximab.1 .
Severe infusion-related reactions (e.g., angioedema, bronchospasm, cardiac arrest, dyspnea, swelling, hypertension, and hypotension), including life-threatening anaphylaxis, have been reported in patients receiving isatuximab therapy.1 In clinical studies (ICARIA-MM, IKEMA, and IMROZ), infusion-related reactions occurred in 35% of patients receiving isatuximab-irfc-containing regimens; most cases (91%) occurred during the first infusion.1 Grade 1 infusion-related reactions were reported in 6%, grade 2 in 28%, and grade 3 or 4 in 1.2% of patients.1
The most common symptoms associated with infusion-related reactions reported in patients receiving isatuximab-irfc were cough and dyspnea.1 Anaphylaxis developed in less than 1% of patients receiving isatuximab-irfc.1
Isatuximab should be administered only in settings where emergency equipment and appropriate medical support are available for the management of potential infusion-related reactions.1 Vital signs should be monitored frequently during infusions of the drug.1 To minimize the risk of infusion-related reactions, patients receiving isatuximab should be premedicated with acetaminophen, dexamethasone, a histamine H2-antagonist, and diphenhydramine.1
In patients experiencing an infusion-related reaction, interruption of the infusion, reduction in the infusion rate, or permanent discontinuance of isatuximab may be necessary and appropriate treatment and supportive care should be provided as clinically indicated.1
Severe, life-threatening, or fatal infections may occur in patients receiving isatuximab.1 In clinical studies (ICARIA-MM, IKEMA, and IMROZ), serious infections including opportunistic infections occurred in 46% of patients and were fatal in 4.7% of patients.1 The most common type of serious infection was pneumonia, which was reported in 32% of patients.1 Monitor patients for signs and symptoms of infection during isatuximab therapy and administer appropriate treatment.1 Administer prophylactic antimicrobials.1 -
Neutropenia has been reported frequently in patients receiving isatuximab-containing regimens in clinical studies.1 In the ICARIA-MM, IKEMA, and IMROZ studies, neutropenia occurred in 81% of patients receiving isatuximab-irfc and was grade 3 or 4 in 52% of patients.1 Febrile neutropenia or neutropenic infections occurred in 4 or 12% of patients receiving isatuximab-irfc, respectively.1
Complete blood cell counts (CBCs) should be periodically monitored during isatuximab therapy.1 Antibacterial and antiviral prophylaxis should be considered.1 If neutropenia occurs, clinicians should monitor for signs or symptoms of infection.1 Temporary interruption of isatuximab may be necessary if neutropenia occurs during therapy with the drug.1 Use of growth factors to treat neutropenia should be administered as clinically indicated.1
Development of Second Primary Malignancy
Second primary malignancies have been reported in 12% patients receiving isatuximab-containing regimens in clinical studies (ICARIA-MM, IKEMA, and IMROZ).1 The most common second primary malignancies were skin cancers and solid tumors other than skin cancers.1 Some patients who developed nonmelanoma skin cancer while receiving isatuximab were able to continue treatment after resection of the cancer.1 Patients should be monitored for development of second primary malignancies.1
Interference with Laboratory Testing
Because isatuximab binds to CD38, a protein expressed on the surface of erythrocytes, false-positive indirect antiglobulin (Coombs') test results may occur in patients receiving the drug.1 Isatuximab may also interfere with antibody detection tests, antibody identification panels, and antihuman globulin crossmatches.1 In the ICARIA-MM study, positive indirect antiglobulin tests occurred in 68% of patients who were tested; however, blood transfusions were administered without evidence of hemolysis.1 In clinical trials, the time to resolution of positive indirect antiglobulin tests following discontinuance of an anti-CD38 monoclonal antibody (i.e., daratumumab, isatuximab) ranged from 1-9 months.7 Determination of ABO and Rh blood type is not affected by isatuximab therapy.1
Blood typing and screening should be performed prior to initiation of isatuximab to determine the presence of baseline alloantibodies.1, 7 Blood phenotyping should also be considered prior to treatment.1
If blood typing and screening did not occur prior to initiation of isatuximab therapy, clinicians should notify the blood bank to use dithiothreitol-treated red blood cells (RBCs) for blood typing and screening because isatuximab may interfere with serologic testing.1 Clinicians should not assume that a positive indirect antiglobulin test result in a patient receiving isatuximab is a false-positive since RBC alloantibodies may be present.7 If an immediate transfusion is required because of an emergency, non-cross-matched ABO/RhD blood type-compatible RBCs may be administered according to local protocols.1
Serum Protein Electrophoresis and Immunofixation Tests
Isatuximab is an IgG kappa immunoglobulin; therefore, the drug may be incidentally detected on serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) assays used for clinical monitoring of endogenous monoclonal immunoglobulins such as myeloma (M) protein.1, 8 Because the concentration of serum M-protein is generally directly proportional to malignant plasma cell burden,9 interference of isatuximab with SPEP and IFE assays may result in misinterpretation of tumor response in patients with IgG kappa M-protein.1, 3 Detection of therapeutic monoclonal antibodies such as isatuximab may persist for several months after the last infusion of the drug.9
Fetal/Neonatal Morbidity and Mortality
There are no adequate and well-controlled studies of isatuximab in pregnant women; however, based on its mechanism of action, isatuximab may cause fetal harm.1 Immunoglobulin G1 (IgG1) has been shown to cross the placenta; therefore, fetal exposure to isatuximab may occur and decrease bone mineral density or cause depletion of CD38-positive immune cells.1 The manufacturer states that administration of live vaccines to neonates and infants who were exposed to isatuximab in utero should be deferred until a hematology evaluation is completed.1
The combination of isatuximab with pomalidomide or lenalidomide is contraindicated in pregnant women because pomalidomide or lenalidomide may cause birth defects and fetal death.1
In clinical trials evaluating isatuximab-irfc monotherapy or combination therapy in patients with relapsed and/or refractory multiple myeloma, anti-isatuximab antibodies were detected in less than 2% of patients treated with isatuximab-irfc.1, 3 In the ICARIA-MM and IKEMA studies, there were no patients who tested positive for anti-drug antibodies; therefore, neutralizing antibodies were not assessed. No clinically important effects on pharmacokinetics, safety, or efficacy of isatuximab were observed in patients who developed anti-drug antibodies in these studies.1, 3 In the IMROZ study in patients with newly diagnosed multiple myeloma, 8.7% of patients treated with isatuximab developed anti-isatuximab antibodies and 5.9% had neutralizing antibodies; there was a trend towards lower drug exposure in the patients who had antibodies, but this was not considered to be clinically meaningful.1 There was also no meaningful effect of anti-drug antibodies on the safety or efficacy of isatuximab.1
There are no adequate and well-controlled studies in pregnant women; however, based on its mechanism of action and animal studies, isatuximab may cause fetal harm.1
The combination of isatuximab with pomalidomide or lenalidomide is contraindicated in pregnant women because pomalidomide or lenalidomide may cause birth defects and fetal death.1 Refer to the pomalidomide or lenalidomide prescribing information for additional information.1 Pomalidomide and lenalidomide are only available through a REMS program.1
It is not known whether isatuximab is distributed into human milk; however, human IgG is distributed into milk.1 The effects of isatuximab on breast-fed infants or on the production of human milk are unknown.1
Because of the potential for serious adverse reactions to the breastfed child, discontinue breast-feeding when isatuximab is used in combination with pomalidomide or lenalidomide and dexamethasone.1 Refer to the prescribing information for pomalidomide or lenalidomide for additional information.1
Females and Males of Reproductive Potential
Pregnancy should be avoided during isatuximab therapy.1
When isatuximab is used in combination with pomalidomide or lenalidomide, refer to the prescribing information for these drugs for pregnancy testing requirements prior to initiating therapy in females of reproductive potential.1 Females of reproductive potential should be advised to use effective contraceptive methods while receiving isatuximab and for at least 5 months after the last dose.1 Refer to the pomalidomide or lenalidomide labeling for contraception requirements prior to initiating treatment in both females of reproductive potential and in male patients.1
Safety and efficacy of isatuximab have not been established in pediatric patients.1
In clinical studies of isatuximab-irfc in patients with relapsed or refractory myeloma, 56% of patients were 65 years of age or older, and 16% were 75 years of age or older.1 Although no overall differences in safety or efficacy were observed between geriatric and younger adults, the possibility of increased sensitivity to isatuximab in some older individuals cannot be ruled out.1, 15 Of the total number of patients with newly diagnosed multiple myeloma who received isatuximab-irfc in the IMROZ trial, 28% of patients were 75 years of age or older.1 Adverse reactions occurring at a higher frequency in these patients include neutropenia.1
Population pharmacokinetic analysis suggests that mild hepatic impairment (total bilirubin concentration 1-1.5 times the upper limit of normal [ULN] or AST concentration exceeding the ULN) has no clinically meaningful effect on systemic exposure to isatuximab.1, 3
The pharmacokinetic profile of isatuximab has not been established in patients with moderate (total bilirubin concentration exceeding 1.5 times the ULN, but not more than 3 times the ULN, and any AST concentration) or severe (total bilirubin concentration exceeding 3 times the ULN and any AST concentration) hepatic impairment.1
Population pharmacokinetic analysis suggests that renal impairment (estimated glomerular filtration rate [eGFR] less than 90 mL/min per 1.73 m2) has no clinically meaningful effect on systemic exposure to isatuximab.1
The most common adverse reactions (≥20%) reported in patients receiving isatuximab-irfc in combination with pomalidomide and dexamethasone are upper respiratory tract infection, infusion-related reactions, pneumonia, and diarrhea.1 The most common hematology laboratory abnormalities (≥80%) in these patients are decreased hemoglobin, decreased neutrophils, decreased lymphocytes, and decreased platelets.1
The most common adverse reactions (≥20%) in patients receiving isatuximab-irfc in combination with carfilzomib and dexamethasone are upper respiratory tract infection, infusion-related reactions, fatigue, hypertension, diarrhea, pneumonia, dyspnea, insomnia, bronchitis, cough, and back pain.1 The most common hematology laboratory abnormalities (≥80%) in these patients are decreased hemoglobin, decreased lymphocytes, and decreased platelets.1
The most common adverse reactions (≥20%) in patients receiving isatuximab-irfc in combination with bortezomib, lenalidomide and dexamethasone are upper respiratory tract infections, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19.1 The most common hematologic laboratory abnormalities (≥80%) in these patients are decreased hemoglobin, decreased leukocytes, decreased lymphocytes, decreased platelets, and decreased neutrophils.1
No formal drug interaction studies have been performed with isatuximab; however, drugs affecting cytochrome P-450 (CYP) isoenzymes or transport systems are not expected to affect the pharmacokinetics of isatuximab.1, 1, 3
Isatuximab, a chimeric anti-CD38 monoclonal antibody, is an antineoplastic agent.1, 2, 3 The drug is an immunoglobulin G1 (IgG1)-derived monoclonal antibody produced from a mammalian cell line (Chinese hamster ovary) using a fed-batch production process.1, 2 Isatuximab is composed of two identical immunoglobulin kappa light chains and two identical immunoglobulin gamma heavy chains.1, 2 Isatuximab binds specifically to antigen CD38, a transmembrane glycoprotein expressed on the surface of hematopoietic and tumor cells, including multiple myeloma cells.1, 5, 11 Following binding of isatuximab to antigen CD38, the drug inhibits ADP-ribosyl cyclase activity of CD38 and induces apoptosis of tumor cells and activation of immune effector mechanisms (i.e., antibody-dependent cell-mediated cytotoxicity [ADCC], antibody-dependent cellular phagocytosis [ADCP], complement-dependent cytotoxicity [CDC]).1, 11 Isatuximab has demonstrated suppression of CD38-positive T-regulatory cells and, in the absence of CD38-positive tumor cells, activation of natural killer (NK) cells.1, 11 Binding of isatuximab directly induces apoptosis in the absence of cross-linking agents and is independent of effector cells, whereas other anti-CD38 monoclonal antibodies (e.g., daratumumab) may induce apoptosis only in the presence of cross-linking agents.13
In vitro, use of isatuximab in combination with pomalidomide enhanced direct tumor cell killing and ADCC activity compared with isatuximab alone.1, 13 Use of isatuximab in combination with pomalidomide also enhanced antitumor activity compared with either drug alone in human multiple myeloma xenograft models.1, 11, 13
Decreased absolute counts of CD19+ B cells and total NK cells, including inflammatory CD16+ low/CD56+ bright and cytotoxic CD16+ bright/CD56+ dim NK cells, in peripheral blood have been observed following therapy with isatuximab-irfc in combination with pomalidomide and dexamethasone in multiple myeloma patients.1
The AUC of isatuximab increases in a dose-proportional manner over a dosage range of 5-20 mg/kg every week for 4 weeks, followed by every 2 weeks and in a greater than dose-proportional manner over a dosage range of 1-20 mg/kg every 2 weeks.1 Steady-state concentrations of the drug are achieved at a median of 18 weeks, with 3.1-fold accumulation.1 Isatuximab is expected to undergo catabolism to small peptides.1 Clearance of isatuximab decreases with increasing dosage and repeated administration, and near elimination of plasma concentrations of the drug is expected in approximately 2 months following the final dose.1 Systemic exposure to isatuximab at steady state decreases with increasing body weight.1 Systemic exposure to isatuximab does not appear to be affected substantially by age (36-85 years) or sex.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Isatuximab-irfc is available only through specialty pharmacies and distributors.6 Contact the manufacturer for additional information.6
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Concentrate, for injection, for IV infusion | 20 mg/mL (100 mg) | ||
20 mg/mL (500 mg) | Sarclisa® | Sanofi-Aventis |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions September 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Sanofi-Aventis U.S. LLC. Sarclisa® (isatuximab-irfc) injection for intravenous use prescribing information. Bridgewater, NJ; 2024 Oct.
2. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 761113Orig1s000: Product quality review. 2020 Jan 31. From FDA website. Accessed 2021 Mar 16. [Web]
3. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 761113Orig1s000: Multi-discipline review. 2020 Feb 28. From FDA website. Accessed 2021 Mar 16. [Web]
4. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2025 Jun 6. [Web]
5. Attal M, Richardson PG, Rajkumar SV et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet . 2019; 394:2096-2107. [PubMed 31735560]
6. Sanofi-Aventis U.S. LLC. Sarclisa® (isatuximab-irfc) acquisition flashcard. From the Sarclisa® website. Accessed 2021 Mar 16. [Web]
7. Lancman G, Arinsburg S, Jhang J et al. Blood Transfusion Management for Patients Treated With Anti-CD38 Monoclonal Antibodies. Front Immunol . 2018; 9:2616. [PubMed 30498492]
8. van de Donk NW, Moreau P, Plesner T et al. Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Blood . 2016; 127:681-95. [PubMed 26631114]
9. Kohlhagen MC, Mills JR, Willrich MAV et al. Clearing drug interferences in myeloma treatment using mass spectrometry. Clin Biochem . 2021; [PubMed 33691184]
11. Dhillon S. Isatuximab: First Approval. Drugs . 2020; 80:905-912. [PubMed 32347476]
12. Varga C, Waldschmidt JM, Gandolfi S et al. Current antibody-based therapies for the treatment of multiple myeloma. Clin Adv Hematol Oncol . 2020; 18:736-748. [PubMed 33406065]
13. Richardson PG, Beksaç M, Spicka I et al. Isatuximab for the treatment of relapsed/refractory multiple myeloma. Expert Opin Biol Ther . 2020; 20:1395-1404. [PubMed 33111607]
14. Dimopoulos MA, Leleu X, Moreau P et al. Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis. Leukemia . 2021; 35:562-572. [PubMed 32444867]
15. Schjesvold FH, Richardson PG, Facon T et al. Isatuximab plus pomalidomide and dexamethasone in elderly patients with relapsed/refractory multiple myeloma: ICARIA-MM subgroup analysis. Haematologica . 2021; 106:1182-1187. [PubMed 32586908]
16. Moreau P, Dimopoulos MA et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021 Jun 19;397(10292):2361-2371. doi: 10.1016/S0140-6736(21)00592-4. Epub 2021 Jun 4. PMID: 34097854.
17. Facon T, Dimopoulos MA, Leleu XP et al. N Engl J Med. 2024 Oct 31;391(17):1597-1609. doi: 10.1056/NEJMoa2400712. Epub 2024 Jun 3. PMID: 38832972.
38. Mikhael J, Ismaila N, Cheung MC, et al. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol. 2019;37(14):1228-1263.
39. PDQ® Adult Treatment Editorial Board. PDQ Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment. Updated February 21, 2025.