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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis.

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March 2, 2020

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761113s000lbl.pdf

On March 2, 2020, the Food and Drug Administration approved Isatuximab-irfc (Sarclisa, sanofi-aventis U.S. LLC) in combination with pomalidomide and dexamethasone for adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

ICARIA-MM (NCT02990338), a multicenter, multinational, randomized, open-label, two-arm, phase 3 study in 307 patients with relapsed and refractory multiple myeloma who had received at least two prior therapies including lenalidomide and a proteasome inhibitor. Patients were randomized (1:1) to receive either isatuximab-irfc with pomalidomide and low-dose dexamethasone (Isa-Pd, 154 patients) or pomalidomide and low-dose dexamethasone (Pd, 153 patients).

The main efficacy outcome measure was progression-free survival (PFS) assessed by an independent committee based on central laboratory data for M-protein and central radiologic imaging review using International Myeloma Working Group criteria. The improvement in PFS represented a 40% reduction in the risk of disease progression or death in patients treated with Isa-Pd (HR 0.596; 95% CI: 0.44-0.81; p=0.0010). Median PFS for the patients who received Isa-Pd was 11.53 months (95% CI: 8.94-13.9) vs 6.47 months (95% CI: 4.47-8.28) for those who received Pd.

The most common adverse reactions (≥20% of patients) were neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, and diarrhea.

The recommended isatuximab-irfc dose is 10 mg/kg as an intravenous infusion every week for 4 weeks followed by every 2 weeks in combination with pomalidomide and dexamethasone until disease progression or unacceptable toxicity.

View full prescribing information for SARCLISA https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761113s000lbl.pdf

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was approved approximately 3 months prior to the FDA goal date.

Isatuximab-irfc was granted orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email This email address is being protected from spambots. You need JavaScript enabled to view it..

Follow the Oncology Center of Excellence on Twitter @FDAOncology

Pharmacist’s Applications to Practice

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

Author: Paul Hughes, PharmD PA-C MCHS
Oncology Pharmacist
WellStar Cobb Hospital
Marietta, GA

What is the potential role for isatuximab-irfc in the treatment of relapsed or refractory multiple myeloma?

  • Isatuximab-irfc is a cytolytic CD38-directed, immunoglobulin G1 (IgG1) chimeric monoclonal antibody (mAb) indicated for the treatment of relapsed or refractory multiple myeloma in combination with pomalidomide and dexamethasone.1
    • CD38 is a type II transmembrane glycoprotein expressed at high levels on both normal plasma cells and multiple myeloma cells.2
    • Daratumumab is the only other CD38-directed mAb currently on the market.
    • Both daratumumab and isatuximab-irfc eliminate myeloma cells via complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis.3, 4
  • Approval of isatuximab-irfc was based on the ICARIA-MM trial, which was a prospective phase 3 multicenter randomized (1:1) open-label active-controlled clinical trial.5
    • The study included 307 patients with a median age of 67 years old and a median of 3 prior therapies. Patients were randomized in a 1:1 fashion to isatuximab-irfc plus pomalidomide plus dexamethasone (154 patients) or pomalidomide and dexamethasone at equivalent dosing (153 patients). Baseline characteristics were similar between groups.
    • Key inclusion criteria included relapsed and refractory multiple myeloma that was unresponsive to lenalidomide and a proteasome inhibitor.
    • Key exclusion criteria included being refractory to previous anti-CD38 mAb or having had previous treatment with pomalidomide.
    • Treatment
      • The treatment group received isatuximab-irfc 10 mg/kg IV on days 1, 8, 15, and 22 in the first 28-day cycle, and then on days 1 and 15 of each 28-day cycle thereafter. This was combined with pomalidomide 4 mg orally on days 1–21 and dexamethasone 40 mg (20 mg if ≥75 years old) orally or intravenously (IV) on days 1, 8, 15, and 22 of each cycle.
      • The control group received pomalidomide and dexamethasone at equivalent dosing.
      • Therapy was continued until disease progression, unacceptable toxicity, or loss of patient consent.
    • Primary endpoint
      • Progression-free survival in the intention-to-treat population was longer in the isatuximab-irfc group (11.5 months) than the control group (6.5 months; hazard ratio [HR] = 0.596; 95% confidence interval [CI] 0.44–0.81; p = .001).
      • Benefit was seen in all prespecified subgroups. Notably these included but were not limited to patients with a poor prognosis and patients refractory to lenalidomide, a proteasome inhibitor, or both lenalidomide and a proteasome inhibitor.
    • Key secondary endpoints
      • Overall survival (at interim analysis): 72% in the isatuximab-irfc group versus 63% in the control group (HR 0.687; 95% CI 0.461–1.023; p = .0631). Median was not reached in either group.
      • Patients with partial response or better: 60% in the isatuximab-irfc group versus 35% in the control group (p < .0001).
    • Safety
      • The most common adverse events reported in the isatuximab-irfc group were anemia (99%), neutropenia (96%), thrombocytopenia (84%), infusion reactions (38%), upper respiratory infection (URI) (28%), diarrhea (26%), bronchitis (24%), and pneumonia (20%). Although p values were not reported, the control group appeared to have lower rates of URI (17%) and bronchitis (9%).
        • Infusion reactions were reversible and generally occurred with the first infusion. Three percent of patients had grade 3 or 4 reactions. No delayed infusion reactions were observed.
        • Although neutropenia rates appeared similar between isatuximab-irfc and the control group (96% vs. 93%), granulocyte-colony stimulating factor was used in 69% in the isatuximab-irfc group versus 53% in the control group.
  • Isatuximab-irfc versus daratumumab
    • There are no head-to-head trials comparing daratumumab and isatuximab-irfc or trials using isatuximab-irfc in patients who are refractory to daratumumab.
    • Key differences between daratumumab and isatuximab-irfc include evidence that
      • isatuximab-irfc can induce direct apoptosis of multiple myeloma cells independent of cross linking, whereas daratumumab requires cross linking2,3,4,6,7,8,9
      • isatuximab-irfc binds to a different epitope of CD38 than daratumumab does7  
      • isatuximab-irfc may activate CDC to some extent, but it appears less potent than daratumumab in this regard.4
    • These differences in mechanism may have important, yet unproven, clinical consequences.
      • The differences in mechanism and epitope binding may make isatuximab-irfc an option for those who have failed daratumumab.
      • Isatuximab-irfc may be a safer medication compared to daratumumab in patients with asthma or chronic obstructive pulmonary disease (COPD), given the possibility that less complement activation may lead to fewer or less severe infusion reactions.10
    • Infusion time
      • Daratumumab has been studied as a rapid infusion over 90 minutes starting with the third infusion; however, patients with severe asthma or COPD were excluded from this trial.11
      • Isatuximab-irfc is infused over 75 minutes starting with the third infusion.1 This approach is based on data from a phase 1b study that does not specify whether patients with asthma or COPD were excluded.12
  • The National Comprehensive Cancer Network lists isatuximab-irfc in combination with pomalidomide and dexamethasone as a category 1 treatment option for patients with relapsed or refractory multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.13

What role can the pharmacist play in the management of patients on isatuximab-irfc?

  • Isatuximab-irfc is dosed at 10 mg/kg IV on days 1, 8, 15, and 22 in the first 28-day cycle, and then on days 1 and 15 of each 28-day cycle thereafter. It is combined with pomalidomide 4 mg orally on days 1–21 and dexamethasone 40 mg (20 mg if patient is ≥75 years old) orally or IV on days 1, 8, 15, 22 of each cycle.
  • Pharmacists can help verify that a pretreatment type and screen have been performed because isatuximab-irfc, like daratumumab, interferes with the indirect Coombs test used in the antibody screening assay.1
  • Pharmacists can monitor laboratory parameters during treatment with isatuximab-irfc.
    • Complete blood counts (CBCs) should be monitored periodically.1 In practice, a CBC is generally drawn prior to each infusion of isatuximab-irfc.
  • Pharmacists can ensure that proper premedication is given 15–60 minutes prior to infusion.1
    • Dexamethasone 40 mg orally or IV (20 mg if patient ≥ 75 years old). This dexamethasone corresponds to the backbone dexamethasone dose.
    • Acetaminophen 650–1,000 mg orally
    • H2 antagonist (famotidine 20 mg)
    • Diphenhydramine 25–50 mg orally or IV
    • There is no recommendation for post-infusion steroid.
  • There are no recommended dose reductions (including for renal or hepatic impairment) for isatuximab-irfc.
    • In the case of grade 4 neutropenia, it is recommended that subsequent doses be delayed and growth factor support provided until the absolute neutrophil count (ANC) is at least 1.0 x 109/L.1
  • Pharmacists can help evaluate for appropriate thromboprophylaxis because of the pomalidomide used in this regimen.

Clinical Pearls

  • Isatuximab-irfc is supplied in 100 mg/5 mL and 500 mg/25 mL single-dose vials.1
  • Isatuximab-irfc is compounded by removing volume of diluent equal to volume of drug from a 250 mL 0.9% normal saline or 5% dextrose bag. The drug is then injected so the final volume is 250 mL.1
  • Administer using IV tubing with a 0.22-micron in-line filter.1
  • The diluted solution is stable for 48 hours refrigerated or 8 hours (including infusion time) at room temperature.1
  • Isatuximab-irfc has a specific protocol for infusion rates.1
    • First infusion: Begin at 25 mL/hour; if no infusion-related reaction after 60 minutes, then increase by 25 mL/hour every 30 minutes to a maximum rate of 150 mL/hour.
    • Second infusion (if no prior reaction): Begin at 50 mL/hour; if no infusion-related reaction after 30 minutes, then increase by 50 mL/hour for 30 minutes and then by 100 mL/hour to maximum rate of 200 mL/hour (i.e., 50 mL/hour for 30 minutes, then 100 mL/hour for 30 minutes, then 200 mL/hour).
    • Subsequent infusions (if no prior reaction): Infuse at 200 mL/hour.
  • Isatuximab-irfc has a patient assistance program through CareASSIST.14

References

  1. Sarclisa (isatuximab-irfc) [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2020.
  2. van de Donk NWCJ, Usmani SZ. CD38 Antibodies in multiple myeloma: mechanisms of action and modes of resistance. Front Immunol. 2018;9:2134.
  3. Deckert J, Wetzel MC, Bartle LM, et al. SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies. Clin Cancer Res. 2014 Sep 1;20(17):4574-4583.
  4. van Bueren JL, Jakobs D, Kaldenhoven N, et al. Direct in vitro comparison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984 and Ab79. Blood. 2014;124(21):3474.
  5. Attal M, Richardson PG, Rajkumar SV, et al. ICARIA-MM study group. 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 Dec 7;394(10214):2096-2107.
  6. Jiang H, Acharya C, An G, et al. SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia. 2016 Feb;30(2):399-408.
  7. Trudel S. Incorporating isatuximab in the treatment of multiple myeloma. Lancet. 2019 Dec 7;394(10214):2045-2047.
  8. Moreno L, Perez C, Zabaleta A, et al. The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma. Clin Cancer Res. 2019 May 15;25(10):3176-3187.
  9. Overdijk MB, Jansen JH, Nederend M, et al. The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via Fcγ receptor-mediated cross-linking. J Immunol. 2016 Aug 1;197(3):807-813.
  10. Richardson P, Smith E. EHA 2019 | ICARIA MM: efficacy and safety of isatuximab, pomalidomide and dexamethasone in patients with RRMM. Available at https://multiplemyelomahub.com/medical-information/eha-2019-icaria-mm-efficacy-and-safety-of-isatuximab-pomalidomide-and-dexamethasone-in-patients-with-rrmm. Published June 20, 2019. Accessed April 12, 2020.
  11. Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130(8):974-981.
  12. Usmani S, Karanes C, Bensinger WI, et al. Isatuximab short duration fixed volume infusion combination therapy for relapsed/refractory multiple myeloma (RRMM): phase 1b feasibility/safety study. Clin Lymphoma Myeloma Leuk. 2019;19(10):e283.
  13. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 4.2020 (May 8, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed April 9, 2020.
  14. CareASSIST by Sanofi Genzyme for SARCLISA (isatuximab-irfc). Available at https://www.sanoficareassist.com/sarclisa. Accessed April 12, 2020.
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