Oncology Overview: Isatuximab-irfc (Sarclisa) for Relapsed/Refractory Multiple Myeloma

Isatuximab-irfc (Sarclisa; sanofi-aventis US LLC) is a targeted monoclonal antibody approved for patients with relapsed and refractory multiple myeloma—the second most common blood cancer.^1,2

More than 130,000 Americans are affected by multiple myeloma, and approximately 32,000 patients are diagnosed each year.¹ Most patients will relapse because multiple myeloma is incurable.³

Indications and Dosage

Isatuximab is used in combination with pomalidomide (Pomalyst; Celgene) and dexamethasone (IPd) for patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor.⁴ Isatuximab is also indicated in combination with carfilzomib (Kyprolis; Amgen) and dexamethasone (IKd) for patients who have received 1 to 3 prior lines of therapy.⁴

The recommended dose of isatuximab is 10 mg/kg—using actual body weight—as an intravenous (IV) infusion.⁴ Health care professionals administer the infusion every week for 4 weeks in cycle 1 (days 1, 8, 15, and 22), followed by every 2 weeks in cycle 2 (days 1, 15, and beyond), until disease progression or unacceptable toxicity.⁴ The first 2 infusions are run over 3 to 4 hours, but the remaining infusions are approximately 75 minutes.²

Mechanism of Action

Isatuximab works in 3 ways:^2,5

1. Finds and binds to cell-surface protein CD38 (widely expressed on myeloma cells), exposing them for elimination by the immune system.
2. Boosts the immune system, making it more difficult for myeloma cells to survive.
3. Directly kills myeloma cells.

FDA Approval

The FDA first approved IPd in March 2020 based on data from phase 3 clinical trial ICARIA-MM.^2,4 Progression-free survival (PFS) was the main efficacy outcome measure.² Researchers discovered a 40% reduction in the risk of disease progression or death (p = 00010).^1,2

The second approval in March 2021 was based on the IKEMA efficacy and safety trial using IKd.^3,4 Researchers found a 45% reduction in the risk of disease progression or death (p = 0.0032).^3,4

Adverse Effects (AEs)

The most common AEs are neutropenia, upper respiratory tract infection (including pneumonia), infusion reactions, and diarrhea.^2,4

Health care providers monitor neutrophil count periodically, and providers may give granulocyte colony-stimulating factor to increase white blood cell production.² Antibiotics or antivirals can help prevent infection.¹

Providers manage infusion related reactions with premedication using dexamethasone, acetaminophen, H₂ antagonists, and diphenhydramine (see Table 1).⁴

Premedications are administered 15 to 60 minutes prior to starting isatuximab infusion.⁴ Reactions may require health care professionals to slow or stop infusion, or completely terminate treatment with isatuximab.¹

Patients need to prevent dehydration caused by diarrhea by drinking enough water.² The American Society of Clinical Oncology recommends patients receiving cancer treatment drink at least 8 cups of water each day.⁶

Unique to IKd, common AEs include fatigue, hypertension, dyspnea, insomnia, bronchitis, cough, and back pain.⁴

Furthermore, patients treated with isatuximab have a risk of new primary cancers (overall incidence is 3.6%).⁴ Patients may experience heart failure during treatment with IKd.⁴ Changes in blood tests can occur affecting blood typing results.⁴

Isatuximab binds to CD38 on red blood cells (RBCs) and may result in a false positive indirect antiglobulin test (indirect Coombs test). Blood banks can resolve this interference with blood compatibility testing by using dithiothreitol-treated RBCs.⁴

Pregnancy and Lactation

Isatuximab is contraindicated in pregnant women and can cause fetal harm.⁴ Lactating women should not breastfeed during treatment.⁴ Pharmacists should advise female patients of reproductive age to use contraception during treatment and for at least 5 months following the last dose.⁴

REFERENCES

1. FDA approves Sarclisa (isatuximab-irfc) for patients with relapsed multiple myeloma [News release]. sanofi-aventis U.S. LLC. March 2, 2020. Accessed July 16, 2021. https://www.sanofi.com/en/media-room/press-releases/2020/2020-03-02-19-51-16

2. Understanding SARCLISA. International Myeloma Foundation. Published June 2020. Accessed July 15, 2021. https://imf-d8-prod.s3.us-west-1.wasabisys.com/2020-06/U-Sarclisa.pdf

3. FDA approves Sarclisa (isatuximab) in combination with carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma [News release]. sanofi-aventis U.S. LLC. March 31, 2021. Accessed July 16, 2021. https://www.sanofi.com/en/media-room/press-releases/2021/2021-03-31-23-15-00-2202919

4. Sarclisa. Prescribing information. sanofi-aventis U.S. LLC; 2021. Accessed July 15, 2021.

5. How Sarclisa works. sanofi-aventis U.S. LLC. Updated June 2021. Accessed July 16, 2021. https://www.sarclisa.com/how-sarclisa-works

6. The importance of hydration. American Society of Clinical Oncology (ASCO). July 1, 2009. Accessed July 17, 2021. https://www.cancer.net/blog/podcasts/importance-hydration