U.S. Food and Drug Administration (FDA)-Approved Indications

Isatuximab-irfc (Sarclisa), a CD38-directed cytolytic antibody, is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody (mAb) which binds to CD38 expressed on the surface of hematopoietic and tumor cells, including multiple myeloma cells. Furthermore, isatuximab-irfc induces apoptosis of tumor cells and activation of immune effector mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC) (sanofi-aventis, 2021).

On March 02, 2020, the U.S. Food and Drug Administration approved Sarclisa (isatuximab-irfc), in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. I

, administered through intravenous (IV) infusion, is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumor activity via multiple mechanisms of action. In a phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone.

The FDA approved

based on the results of a r

The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. Patients were randomly assigned (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomization was done using interactive response technology and stratified according to the number of previous lines of treatment (2-3 vs >3) and age (<75 years vs ≥75 years). Treatments were assigned based on a permuted blocked randomization scheme with a block size of four. The isatuximab-pomalidomide-dexamethasone group received isatuximab intravenously on days 1, 8, 15, and 22 in the first 28-day cycle, then on days 1 and 15 in subsequent cycles. Both groups received oral pomalidomide on days 1 to 21 in each cycle, and oral or intravenous dexamethasone on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. Dose reductions for adverse reactions were permitted for pomalidomide and dexamethasone, but not for isatuximab. The primary endpoint was progression-free survival, determined by an independent response committee and assessed in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. Between Jan 10, 2017, and Feb 2, 2018, three hundred and seven patients were randomly assigned to treatment: 154 to isatuximab-pomalidomide-dexamethasone, and 153 to pomalidomide-dexamethasone. At a median follow-up of 11·6 months (IQR 10·1-13·9), median progression-free survival was 11·5 months (95% CI 8·9-13·9) in the isatuximab-pomalidomide-dexamethasone group versus 6·5 months (4·5-8·3) in the pomalidomide-dexamethasone group; hazard ratio 0·596, 95% CI 0·44-0·81; p=0·001 by stratified log-rank test. The most frequent treatment-emergent adverse events (any grade; isatuximab-pomalidomide-dexamethasone vs pomalidomide-dexamethasone) were infusion reactions (56 [38%] vs 0), upper respiratory tract infections (43 [28%] vs 26 [17%]), and diarrhea (39 [26%] vs 29 [20%]). Adverse events with a fatal outcome were reported in 12 patients (8%) in the isatuximab-pomalidomide-dexamethasone group and 14 (9%) in the pomalidomide-dexamethasone group. Deaths due to treatment-related adverse events were reported for one patient (<1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection). The authors concluded the addition of isatuximab to pomalidomide-dexamethasone significantly improves progression-free survival in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor.

On March 31, 2021, the U.S. Food and Drug Administration (FDA) approved Sarclisa (isatuximab) in combination with carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received one to three prior lines of therapy. The FDA approval was based on data from the Phase 3 IKEMA study. This study consisted of a randomized, multi-center, open label clinical trial of 302 patients with relapsed multiple myeloma spanning across 69 centers and 16 countries. Notably, the addition of Sarclisa to carfilzomib and dexamethasone (Sarclisa combination therapy) reduced the risk of disease progression or death by 45% versus standard care of carfilzomib with dexamethasone alone in patients with multiple myeloma. No statistically significant difference in overall response rate was noted and which was evidenced as 86.6% for the Sarclisa combination therapy arm versus 82.9% for the carfilzomib with dexamethasone arm. The rate of complete response was 39.7% in the Sarclisa combination therapy arm and 27.6% in the carfilzomib with dexamethasone arm. Serious adverse reactions that appeared in more than 5% of patients who received Sarclisa combination therapy were pneumonia (25%) and upper respiratory tract infections (9%) (Sanofi, 2021).

Acute Lymphoblastic Leukemia

Wang and colleagues (2021) reported the pharmacologic effects of isatuximab on T- and B-cell acute lymphoblastic leukemia (ALL). These researchers analyzed CD38 expression in 50-T-ALL and 50 B-ALL clinical samples, and 16 T-ALL and 11 B-ALL cell lines. They primarily focused on in-vitro assessments of isatuximab-mediated ADCC and ADCP. In-vivo assessment of isatuximab activity was carried out in several ALL xenograft models, including disseminated and subcutaneous tumor models in female C.B-17 severe combined immunodeficiency (SCID) mice. This study showed that most patients (90 % to 100 %) carried CD38+ blasts independent of disease burden. The median CD38 receptor density on abnormal lymphoblasts is 41,026 copies/cell on T-ALL and 28,137 copies/cell on B-ALL, respectively. In patients with T-ALL, there was a significant increase of CD38 expression in abnormal blasts compared with normal T cells. High-level CD38 receptor density (RD) was critical to trigger effective isatuximab-mediated ADCC against target ALL cells. Furthermore, a correlation between CD38 RD and isatuximab-mediated ADCP was demonstrated. In the disseminated CD38+, T-ALL, and B-ALL xenograft models, isatuximab was able to induce robust anti-tumor activity, even at low doses. The authors concluded that the findings of this study showed that isatuximab had significant in-vitro and in-vivo activity against ALL cells with robust ADCC and ADCP effects that were associated with CD38 expression levels in both T-ALL and B-ALL.

Boissel et al (2022) stated that the poor prognosis of T-cell ALL (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in older adults and patients with relapsed/refractory (r/r) illness is an unmet clinical need, as there is no defined standard of care (SOC) and there are few therapeutic options. Abnormally elevated CD38 expression in T-ALL and T-LBL is associated with tumor expansion and disease development, making CD38 a potential target for anti-T-ALL and T-LBL treatment. Isatuximab is a monoclonal antibody that binds to a specific epitope on CD38. In an open-label, one-arm, multi-center, phase-II clinical trial, these researchers examined the safety and effectiveness of isatuximab monotherapy in patients with r/r T-ALL or T-LBL. The primary endpoint was the overall response rate (ORR). An interim analysis based on the safety and effectiveness of isatuximab in the first 19 patients enrolled was scheduled; however, only 14 patients were enrolled in the study. No patient achieved complete response (CR) or CR with incomplete peripheral recovery. Most patients (11 [78.6 %]) developed progressive disease and had progressive disease as their best response. A total of 10 (71.4 %) patients had treatment emergent adverse events (TEAEs) considered treatment-related, with infusion reactions as the most frequent drug-related TEAE, occurring in 8 (57.1 %) patients. The authors concluded that despite the low effectiveness of isatuximab in this phase-II clinical trial, it is likely that the use of immunotherapy medication in T-ALL will be expanded via logically targeted approaches, together with advances in the design of T-cell therapy and clinical experience and will provide restorative options beyond chemotherapy and targeted treatments.

The authors stated that the main drawback of this trial was that it included heavily pre-treated patients who had received multiple previous lines of therapy. A total of 14 patients were treated; however, the study was stopped due to lack of effectiveness of isatuximab in adult patients with r/r T‐ALL or T‐LBL. Most patients (n = 12, 85.7 %) had progressive disease during the treatment period, making it unlikely to achieve greater than 3/19 responses needed to continue the study; 2 (14.3 %) patients discontinued the study due to AEs. Most patients, 8 (57.1 %) patients had mild infusion reactions and 1 (7.1 %) patient developed a cytokine release syndrome (CRS). These investigators noted that T‐ALL is an aggressive disease and the expression of CD38 is insufficient to allow a biologic agent to be effective as monotherapy in heavily pre-treated patients. Combination therapy with chemotherapy may be more effective in patients who have not received previous rounds of intensive treatment. Most patients in this phase-II clinical trial discontinued treatment before optimal blood levels of isatuximab could be reached. The poor response and safety profile of isatuximab monotherapy in this study resulted in an unsatisfactory risk/benefit ratio for this cohort of patients.

Duchenne Muscular Dystrophy

de Zelicourt et al (2022) noted that Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration. Two important deleterious features are a Ca2+ dysregulation linked to Ca2+ influxes associated with ryanodine receptor hyper-activation, and a muscular nicotinamide adenine dinucleotide (NAD+ ) deficit. These researchers identified that deletion in mdx mice of CD38, a NAD+ glycohydrolase-producing modulators of Ca2+ signaling, resulting in a fully restored heart function and structure, with skeletal muscle performance improvements, associated with a reduction in inflammation and senescence markers. Muscle NAD+ levels were also fully restored, while the levels of the 2 main products of CD38, nicotinamide and ADP-ribose, were reduced, in heart, diaphragm, and limb. In cardiomyocytes from mdx/CD38-/- mice, the pathological spontaneous Ca2+ activity was reduced, as well as in myotubes from DMD patients treated with isatuximab, a monoclonal anti-CD38 antibody. The authors concluded that treatment of mdx and utrophin-dystrophin-deficient (mdx/utr-/- ) mice with CD38 inhibitors resulted in improved skeletal muscle performances. These researchers demonstrated that CD38 actively contributes to DMD physiopathology; they proposed that a selective anti-CD38 therapeutic intervention could be highly relevant to develop for patients with DMD.

Isatuximab plus Atezolizumab for the Treatment of Solid Tumors

Simonelli et al (2022) noted that the anti-CD38 antibody isatuximab is FDA-approved for the treatment of relapsed/refractory multiple myeloma (MM); however, there are no data on its effectiveness in solid tumors. In a phase-I/II clinical trial, these researchers examined the activity and safety of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Phase-I of this Trial examined safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase-II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1,200 mg i.v. every 3 weeks. Phase-II of this Trial used a Simon's 2-stage design to assess the ORR or progression-free survival (PFS) rate at 6 months (GBM cohort). Interim analysis was performed at 6 months following 1st dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor micro-environment (TME). A total of 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase-I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities (DLTs) were observed, and RP2D was confirmed. Most patients experienced 1 or more TEAE, with 48.5 % or less being grade-3 or higher. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on pre-specified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared following treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. The authors concluded that Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. These researchers stated that based on clinical data, the combination of Isa + Atezo had limited activity in patients with treatment-resistant or treatment-refractory solid tumors.

The authors stated that this study was limited by the small number of patients enrolled with each tumor type and the early study termination based on the interim analysis. Patients were not selected based on the presence of a putative target/biomarker, i.e., CD38 expression. Moreover, these researchers stated that additional studies are needed to further examine underlying biomarkers that may inform treatment selection and predict benefit of combination therapy with anti-CD38 and anti-PD-1/PD-L1 agents in patients with solid tumors, including patients with progression after an initial response to PD-1/PD-L1 blockade.

Isatuximab plus Cemiplimab for the Treatment of Solid Tumors

Zucali et al (2022) stated that pre-clinical data suggested that concurrent treatment of anti-CD38 and anti-programmed death 1 (PD-1)/PD-L1 antibodies substantially reduce primary tumor growth by reversing T-cell exhaustion and thus enhancing anti-PD-1/PD-L1 efficacy. In a phase I/II clinical trial, these researchers enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) or advanced non-small cell lung cancer (NSCLC). The primary aims of the phase-I study were to examine the safety and tolerability of isatuximab (anti-CD38 monoclonal antibody)+cemiplimab (anti-PD-1 monoclonal antibody, Isa+Cemi) in patients with mCRPC (naïve to anti-PD-1/PD-L1 therapy) or NSCLC (progressed on anti-PD-1/PD-L1-containing therapy). The phase-II study employed Simon's 2-stage design with response rate as the primary endpoint. An interim analysis was planned after the first 24 (mCRPC) and 20 (NSCLC) patients receiving Isa+Cemi were enrolled in the phase-II study. Safety, immunogenicity, pharmacokinetics, pharmacodynamics, and anti-tumor activity were assessed, including CD38, PD-L1, and tumor-infiltrating lymphocytes in the TME, and peripheral immune cell phenotyping. Isa+Cemi showed a manageable safety profile with no new safety signals. All patients experienced 1 or more TEAE. Grade-3 or higher AEs occurred in 13 (54.2 %) patients with mCRPC and 12 (60.0 %) patients with NSCLC. Based on Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria, assessment of best overall response with Isa+Cemi in mCRPC revealed no CRs, 1 (4.2 %) unconfirmed partial response (PR), and 5 (20.8 %) patients with stable disease (SD). Per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1, patients with NSCLC receiving Isa+Cemi achieved no CR or PR, and 13 (65 %) achieved SD. In post-therapy biopsies obtained from patients with mCRPC or NSCLC, Isa+Cemi treatment resulted in a reduction in median CD38+ tumor-infiltrating immune cells from 40 % to 3 %, with no consistent modulation of PD-L1 on tumor cells or Tregs in the TME. The combination triggered a significant increase in peripheral activated and cytolytic T cells but, interestingly, decreased natural killer (NK) cells. The authors concluded that the findings of this study suggested that CD38 and PD-1 modulation by Isa+Cemi exhibited a manageable safety profile, reduced CD38+ immune cells in the TME, and activated peripheral T cells; however, such CD38 inhibition was not associated with significant anti-tumor activity; a lack of effectiveness was observed in these small cohorts of patients with mCRPC or NSCLC. The authors stated that the limitation of this study was the small number of patients enrolled with each tumor type. These researchers stated that additional studies are needed to further examine underlying biomarkers that may inform treatment selection and predict benefit from combination therapy with anti-CD38 and anti-PD-1/PD-L1 agents.

Light Chain Amyloidosis

Rodriguez et al (2022) noted that light chain (AL) amyloidosis is challenging to diagnose, and it should be considered a cardiac emergency. There has been a great deal of advances in the treatment of AL amyloidosis from initial descriptions of melphalan therapy until the recent approval of the 1st AL amyloidosis specific drug (daratumumab). Comprehension of the pathophysiology and biology of AL amyloidosis is crucial to understanding the major therapeutic targets in which light chain stability remains as a major key target of therapy. Organ dysfunction is a result not only from disruption of organ architecture but also direct cellular toxicity. Novel anti-plasma cell agents for AL like isatuximab (anti CD-38 monoclonal antibody), belantamab (anti-BCMA monoclonal antibody), and elotuzumab (anti-SLAMF7 monoclonal antibody) are currently under investigation. The authors concluded that both diagnostic and therapeutic advances made the future of AL management bright while acknowledging the complexity of this patient population and focusing on a multi-disciplinary approach.

Soft Tissue Plasmacytoma

In the phase-III ICARIA-MM and IKEMA Trials, Beksac et al (2022) demonstrated that isatuximab (Isa) plus pomalidomide (P) and dexamethasone (d; Isa-Pd) or carfilzomib (K) and d (Isa-Kd) improved progression-free survival (PFS) versus Pd or Kd in patients with relapsed and/or refractory multiple myeloma (MM). In this post-hoc analysis of patients with soft-tissue plasmacytomas, these researchers examined the effectiveness of Isa-Pd/Isa-Kd using central radiology and central laboratory assessments. Given the low incidence of soft-tissue plasmacytomas (7.8 %, ICARIA-MM; 6.3 %, IKEMA), effectiveness data were pooled across the 2 studies. PFS (HR, 0.47; 95 % CI: 0.21 to 1.08), ORR (50.0 % versus 17.7 %), and very good partial response (PR) or better rate (26.9 % vs 11.8 %) were improved with Isa-Pd/Isa-Kd versus Pd/Kd, with consistent improvements within individual studies. Patients with soft-tissue plasmacytomas who received Isa-Pd/Isa-Kd had similar median PFS compared with those without soft-tissue plasmacytomas and received Pd/Kd. Safety is reported individually per study. Longer median treatment duration and more Grade ≥ 3 treatment-emergent adverse events occurred in the Isa versus control arms in ICARIA-MM (36.9 vs 8.4 weeks; 85.7 % vs 70.0 %) and IKEMA (41.9 vs 29.9 weeks; 100.0 % vs 57.1 %); however, Isa did not increase the percentage of patients with fatal events or drug discontinuation. Isa-Pd or Isa-Kd is a potential new treatment option and partially overcomes the poor prognosis associated with soft-tissue plasmacytomas in relapsed and/or refractory multiple myeloma.

Requires Precertification:

Precertification of Sarclisa (isatuximab-irfc) is required of all Aetna participating providers and members in applicable plan designs. For precertification of Sarclisa (isatuximab-irfc), call (866) 752-7021 (Commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see

For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.

Criteria for Initial Approval

Aetna considers isatuximab-irfc (Sarclisa) therapy medically necessary for multiple myeloma in

of the following settings:

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

Continuation of Therapy

Aetna considers continuation of isatuximab-irfc (Sarclisa) therapy medically necessary in members requesting reauthorization for a medically necessary for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Isatuximab-irfc is available as Sarclisa as 100 mg/5 mL (20 mg/mL) solution in single-dose vial and 500 mg/25 mL (20 mg/mL) solution in single-dose vial for intravenous infusion.

Multiple Myeloma

The recommended dose of Sarclisa is 10 mg/kg actual body weight administered as an intravenous infusion in combination with pomalidomide and dexamethasone or in combination with carfilzomib and dexamethasone. Each treatment cycle consists of a 28-day period. Treatment is repeated every week for 4 weeks followed by every 2 weeks until disease progression or unacceptable toxicity.

Source: sanofi-aventis, 2022

Experimental and Investigational

Aetna considers istuximab plus atezolizumab experimental and investigational for the treatment of solid tumors (including glioblastoma, head and neck squamous cell carcinoma. hepatocellular carcinoma, non-small cell lung cancer, ovarian cancer, and prostate cancer).

Aetna considers isatuximab plus cemiplimab experimental and investigations for the treatment of solid tumors (including glioblastoma, head and neck squamous cell carcinoma. hepatocellular carcinoma, non-small cell lung cancer, ovarian cancer, and prostate cancer).

Aetna considers isatuximab experimental and investigational for the treatment of other conditions/diseases including the following (not an all-inclusive list):