Coverage Policy Manual
Policy #: 2020008
Category: Pharmacy
Initiated: April 2020
Last Review: April 2022
  Isatuximab-irfc (e.g., Sarclisa)

Description:
Isatuximab-irfc is a CD38 directed cytolytic immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to CD38 expressed on the surface of hematopoietic and tumor cells, including multiple myeloma MM) cells.  It 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 cytoxicity (CDC).  Isatuximab-irfc can activate natural killer (NK) cells in the absence of CD38-positive target tumor cells and suppresses CD38-positive T-regulatory cells.
 
Regulatory Status
 
Isatuximab-irfc (e.g., SARCLISA®) was approved by the FDA on March 2, 2020.  It is indicated in combination with pomalidomide and dexamethasone, for the treatment of adult patients with MM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor (PI).  Isatuximab-irfc was also granted Orphan Drug designation.
 
On March 31, 2021, the Food and Drug Administration approved Isatuximab-irfc (e.g., Sarclisa) in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.
 
Coding
 
On October 1, 2020, J9227 injection isatuximab irfc, 10 mg will be effective. Services billed as of October 1, 2020 and after will be expected to be billed with this code.

Policy/
Coverage:
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
 
Effective January 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Isatuximab-irfc meets member benefit certificate primary coverage for previously treated multiple myeloma for relapse or progressive disease when documentation is submitted to support that ALL the following criteria are met:
 
    1. In combination with pomalidomide and dexamethasone (NCCN 1), for the treatment of adult patients with multiple myeloma meeting all the following criteria:
 
        1. Has not failed treatment with previous anti-CD38 therapy (e.g., daratumumab, etc) (Attal, 2019); AND
        2. Received at least two prior therapies including an immunomodulary agent (e.g., lenalidomide, etc.) (NCCN 1) and a proteasome inhibitor (e.g., bortezuomib, ixazomib, barfilzomib, etc) (NCCN 1; Sarclisa, 2020; Attal, 2019); AND
        3. Documentation will be submitted to support the above criteria; AND
        4. Initial coverage will be for 6 months.
 
OR
 
2.  In combination with carfilzomib and dexamethasone (NCCN 2), for the treatment of adult patients with relapsed or refractory multiple myeloma meeting all the following criteria:
 
        1. Has not failed treatment with previous anti-CD38 therapy (e.g., daratumumab, etc) (Attal, 2019; AND
        2. Received 1 to 3 prior lines of therapy (FDA label; Attal, 2019); AND
        3. Documentation will be submitted to support the above criteria; AND
        4. Initial coverage will be for 6 months.
 
Continuation of coverage (for 1year) will be contingent on the individual meeting ALL the following:
 
      1. Continues to meet the initial approval criteria; AND
      2. Documentation indicating disease response to treatment, by stabilization of disease and decrease in size of tumor or tumor spread; AND
      3. Absence of unacceptable toxicity from the drug, including severe infusion reactions such as anaphylactic reactions, neutropenia, secondary primary malignancies, etc.
 
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
 
Dosage and Administration
 
The recommended dose of Isatuximab-irfc is 10 mg/kg as an intravenous infusion every week for 4 weeks followed by every 2 weeks until disease progression or unacceptable toxicity. See full prescribing information for drugs used in combination and schedule.
 
Note: Each treatment cycle consists of a 28-day period.  Treatment is repeated until disease progression or unacceptable toxicity.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Isatuximab-irfc does not meet member benefit certificate primary coverage criteria for any indication other than those outlined above.
 
For members with contracts without primary coverage criteria, isatuximab-irfc is considered investigational for any indication other than those outlined above.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective April 2021-December 1, 2021
 
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Isatuximab-irfc (SARCLISA®) meets member benefit certificate primary coverage for multiple myeloma when documentation is submitted to support that ALL of the following criteria are met:
 
    1. In combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma with the following criteria:
        1. Has not failed treatment with previous anti-CD38 therapy (e.g., daratumumab, etc).
        2. Received at least two prior therapies including an immunomodulary agent (e.g., lenalidomide, etc.) and a proteasome inhibitor (e.g., bortezuomib, ixazomib, barfilzomib, etc)
        3. Documentation will be submitted to support the above criteria.
        4. Initial coverage will be for 6 months.
 
OR
 
2. In combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma with the following criteria:
        1. Received 1 to 3 prior lines of therapy
        2. Documentation will be submitted to support the above criteria.
        3. Initial coverage will be for 6 months.
 
Continuation of coverage (for 1year) will be contingent on the individual meeting ALL of the following:
 
        1. Continues to meet the initial approval criteria
        2. Documentation indicating disease response to treatment, by stabilization of disease and decrease in size of tumor or tumor spread.  
        3. Absence of unacceptable toxicity from the drug, including severe infusion reactions such as anaphylactic reactions, neutropenia, secondary primary malignancies, etc.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
 
Dosage and Administration
 
The recommended dose of SARCLISA is 10 mg/kg as an intravenous infusion every week for 4 weeks followed by every 2 weeks until disease progression or unacceptable toxicity. See full prescribing information for drugs used in combination and schedule.
 
Note: Each treatment cycle consists of a 28-day period.  Treatment is repeated until disease progression or unacceptable toxicity.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Isatuximab-irfc (SARCLISA®) does not meet member benefit certificate primary coverage criteria for any other indication than those outlined above.
 
For members with contracts without primary coverage criteria, isatuximab-irfc (SARCLISA®) is considered investigational for any other indication.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective April 2020- March 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Isatuximab-irfc (SARCLISA®) meets member benefit certificate primary coverage for multiple myeloma when documentation is submitted to support that ALL of the following criteria are met:
 
    1. Individual is 18 yrs of age or older.
    2. Has a confirmed diagnosis of multiple myeloma and will be used in combination with pomalidomide and dexamethasone.
    3. Has not failed treatment with previous anti-CD38 therapy (e.g., daratumumab, etc).
    4. Received at least two prior therapies including an immunomodulary agent (e.g., lenalidomide, etc.) and a proteasome inhibitor (e.g., bortezuomib, ixazomib, barfilzomib, etc)
    5. Documentation will be submitted to support the above criteria.
    6. Initial coverage will be for 6 months.
 
Continuation of coverage (for 1year) will be contingent on the individual meeting ALL of the following:
 
    1. Continues to meet the initial approval criteria
    2. Documentation indicating disease response to treatment, by stabilization of disease and decrease in size of tumor or tumor spread.  
    3. Absence of unacceptable toxicity from the drug, including severe infusion reactions such as anaphylactic reactions, neutropenia, secondary primary malignancies, etc.
 
NCCN 1 and 2A recommendations in accordance with Coverage Policy #2000030.
 
Dosage and Administration
 
The recommended dose of Isatuximab-irfc us 10 mg/kg intravenous infusion in combination with pomalidomide and dexamethasone until disease progression or unacceptable toxicity:
 
    • Weekly cycle 1 (four doses total; Days 1, 8, 15 & 22)
    • Every 2 week cycles 2 and beyond (two doses per cycle; Days 1 & 15).
 
Note: Each treatment cycle consists of a 28-day period.  Treatment is repeated until disease progression or unacceptable toxicity.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Isatuximab-irfc (SARCLISA®) does not meet member benefit certificate primary coverage criteria for any other indication.
 
For members with contracts without primary coverage criteria, isatuximab-irfc (SARCLISA®) is considered investigational for any other indication.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
Multiple myeloma (MM) is characterized by the neoplastic proliferation of clonal plasma cells producing a monoclonal immunoglobulin.  These clonal plasma cells proliferate in the bone marrow and can result in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures.  Additional disease-related complications include hypercalcemia, renal insufficiency, anemia and infections.
For those patients with symptomatic MM initial therapy depends on risk stratification (i.e. high or standard risk disease), eligibility for autologous hematopoietic cell transplantation (HCT), and resources available.  Almost all patients with MM who survive initial treatment will eventually relapse and require further therapy.  Treatment options for those with relapsing remitting MM (RRMM) include HCT, a rechallenge of the previous chemotherapy regimen, or a trial of a new regimen. The decision for the next step in therapy includes risk stratification, prior treatments used, and the duration or response to those treatments.  
In the triple drug regimens that are increasingly the norm for treating MM, patients will typically receive one or two active agents in combination with dexamethasone and are treated until disease progression, after which another dexamethasone containing regimen may be given.
 
The approval for isatuximab-irfc (SARCLISA®) is based on the Phase 3 ICARIA-MM (NCT 02990338) trial which examined the use of Isatuximab-irfc with Pomalyst (pomalidomide) and dexamethasone compared to Pomalyst with dexamethasone (Pd).  ICARIA-MM is an open-label, multicenter, phase 3 trial that included 307 patients with RRMM who had received at least 2 lines of prior therapy (median of 3) and were randomly assigned to receive pomalidomide plus dexamethasone with or without isatuximab-irfc.
 
At a median follow-up of 11.6 months, progression free survival (PFS) was 11.53 months with the isatuximab regimen compared with 6.47 months with Pd alone. PFS was seen across multiple patient subgroups, including patients with high cytogenetic risk, patients refractory to Revlimid, patients refractory to a proteasome inhibitor, am patients refractory to Revlimid and a proteasome inhibitor.   Overall survival (OS) data at 1 year was 72% with the isatuximab arm compared with 63% with Pd-alone arm.   There was also a greater overall response rate in the isatuximab arm of 93% versus 54% in the non-isatuximab arm.  The median duration of treatment was 41 weeks in the isatuximab arm compared to 24.0 weeks in the Pomalyst-alone arm.  56.5% of patients discontinued treatment in the isatuximab arm compared to 74.5% in the Pomalyst alone arm, with progressive disease being the primary reason for discontinuation in both arms.   There was a higher rate of grade 3 or greater adverse events 86.8% of the isatuximab combination arm compared with 70.5% of the Pomalyst only arm. The rate of serious TEAEs were 61.8% versus 53.7% respectively.  
 
2021 Update
The efficacy and safety of SARCLISA in combination with carfilzomib and dexamethasone were evaluated in IKEMA (NCT03275285), a multicenter, multinational, randomized, open-label, 2­arm, phase 3 study in patients with relapsed and/or refractory multiple myeloma. Patients had received one to three prior lines of therapy. Patients were eligible for inclusion if they had an ECOG status of 0-2, platelets ≥50,000 cells/mm3, absolute neutrophil count ≥1 × 109/L, creatinine clearance ≥15 mL/min/1.73 m2 (MDRD formula), AST ≤3 × ULN, and ALT ≤3 × ULN.
 
A total of 302 patients were randomized in a 3:2 ratio to receive either SARCLISA in combination with carfilzomib and dexamethasone (Isa-Kd, 179 patients) or carfilzomib and dexamethasone (Kd, 123 patients). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. SARCLISA 10 mg/kg was administered as an intravenous infusion weekly in the first cycle and every two weeks thereafter. Carfilzomib was administered as an intravenous infusion at the dose of 20 mg/m2 on days 1 and 2; 56 mg/m2 on days 8, 9, 15, and 16 of cycle 1; and at the dose of 56 mg/m2 on days 1, 2, 8, 9, 15, and 16 for subsequent cycles of each 28-day cycle. Dexamethasone (intravenously on the days of isatuximab-irfc and/or carfilzomib infusions, and orally on the other days) 20 mg was given on days 1, 2, 8, 9, 15, 16, 22, and 23 for each 28-day cycle. On the days where both SARCLISA and carfilzomib were administered, dexamethasone was administered first, followed by SARCLISA infusion, then followed by carfilzomib infusion.
Overall, demographic and disease characteristics at baseline were similar between the two treatment groups. The median patient age was 64 years (range 33-90), 9% of patients were ≥75 years, 71% were White, 17% Asian, and 3% Black or African American. The proportion of patients with renal impairment (eGFR<60 mL/min/1.73 m2) was 24% in the Isa-Kd group versus 15% in the Kd group. The International Staging System (ISS) stage at study entry was I in 53%, II in 31%, and III in 15% of patients. Overall, 24% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14), t(14;16) were present in 11%, 14%, and 2% of patients, respectively. In addition, gain(1q21) was present in 42% of patients.
 
The median number of prior lines of therapy was 2 (range 1-4) with 44% of patients who received 1 prior line of therapy. Overall, 90% of patients received prior proteasome inhibitors, 78% received prior immunomodulators (including 43% who received prior lenalidomide), and 61% received prior stem cell transplantation. Overall, 33% of patients were refractory to prior proteasome inhibitors, 45% were refractory to prior immunomodulators (including 33% refractory to lenalidomide), and 21% were refractory to both a proteasome inhibitor and an immunomodulator.
 
The median duration of treatment was 80 weeks for the Isa-Kd group compared to 61 weeks for the Kd group.
 
The efficacy of SARCLISA was based upon PFS. PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the IMWG criteria. The improvement in PFS represented a 45% reduction in the risk of disease progression or death in patients treated with Isa-Kd compared to patients treated with Kd. (FDA, 2020)
 
2022 Update
Patients with relapsed/refractory multiple myeloma (RRMM) experience several relapses and become refractory to successive therapies. In the ICARIA-MM trial (NCT02990338), isatuximab plus pomalidomide-dexamethasone prolonged median progression-free survival (PFS) in patients with RRMM. This subgroup analysis of ICARIA-MM assessed the treatment benefit of isatuximab by prior lines of therapy and refractory status. A total of 307 patients were randomized to isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, then every other week. Standard pomalidomide-dexamethasone doses were given. PFS was assessed by prior lines and refractory status. Overall, 102 (66 %) patients receiving isatuximab-pomalidomide-dexamethasone and 101 (66 %) patients receiving pomalidomide-dexamethasone had received 2-3 prior lines; 52 (34 %) and 52 (34 %) had received >3 prior lines, respectively. Median PFS was higher with isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone for patients who received 2-3 prior lines of therapy (12.3 vs. 7.8 months) and >3 prior lines of therapy (9.4 vs. 4.3 months). Median PFS was higher with isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone for patients who were lenalidomide-refractory (11.4 vs. 5.6 months), lenalidomide-refractory at last line (11.6 vs. 5.7 months), refractory to a proteasome inhibitor (PI) (11.4 vs. 5.6 months), and double-refractory (11.2 vs. 4.8 months). Overall response rate (ORR) in patients receiving isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone was 59.0 % versus 31.4 % in lenalidomide-refractory; 60.2 % versus 32.2 % in PI-refractory; and 58.6 % versus 29.9 % in double-refractory patients. Isatuximab-pomalidomide-dexamethasone improved PFS and ORR regardless of prior lines of therapy or refractory status, consistent with the benefit in the overall population. (Bringhen S, Pour L, Vorobyev V,et.al., 2021)

CPT/HCPCS:
J3490Unclassified drugs
J3590Unclassified biologics
J9227Injection, isatuximab irfc, 10 mg
J9999Not otherwise classified, antineoplastic drugs

References: Attal M, Richardson PG, Rajkumar SV, et al.(2019) 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. The Lancet, December 07, 2019 Volume 394, Issue 10214, 2096 – 2107

Bringhen S, Pour L, Vorobyev V, Vural F, Warzocha K, Benboubker L, Koh Y, Maisnar V, Karlin L, Pavic M, Campana F, Le Guennec S, Menas F, van de Velde H, Richardson PG.(2021) Isatuximab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma according to prior lines of treatment and refractory status: ICARIA-MM subgroup analysis. Leuk Res. 2021 May;104:106576. doi: 10.1016/j.leukres.2021.106576. Epub 2021 Mar 29. PMID: 33839618.

Food and Drug Administration.(2020) Sarclisa prescribing information. Accessed at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761113s003lbl.pdf

Moreau P, Dimopoulos MA, Yong K, Mikhael J, Risse ML, Asset G, Martin T.(2019) Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design. Future Oncol. 2020 Jan;16(2):4347-4358. doi: 10.2217/fon-2019-0431. Epub 2019 Dec 13. PMID: 31833394.

National Comprehensive Cancer Network, Inc. (NCCN)(2021) 2021 Practice Guidelines in Oncology—Multiple Myeloma v.7.2021. Available at https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed August 13, 2021.

SARCLISA® (isatuximab-irfc) [package insert] Sanofi-Aventis U.S. LLC. March 2020

USFDA(2020) FDA Approves New Therapy for Patients with Previously Treated Multiple Myeloma. March 02, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-new-therapy-patients-previously-treated-multiple-myeloma. Last accessed 04/17/2020.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2022 American Medical Association.