On March 2, 2020, the CD-38-directed cytolytic antibody isatuximab-irfc (Sarclisa) was approved for use 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.1,2
Supporting Efficacy Data
Approval was based on findings from the multinational, open-label, phase III ICARIA-MM trial.2,3 In the trial, 307 patients with relapsed and refractory multiple myeloma who had received at least two prior therapies including lenalidomide and a proteasome inhibitor were randomly assigned to receive isatuximab-irfc with pomalidomide and low-dose dexamethasone (Isa-Pd, n = 154) or pomalidomide and low-dose dexamethasone (Pd, n = 153). The main efficacy outcome measure was progression-free survival as assessed by independent review committee based on central laboratory data for M-protein and central radiologic imaging review using International Myeloma Working Group criteria.
The median age of patients was 67 years (range = 36–86 years, 20% ≥ 75 years); 58% were male; 76% were white and 14% were Asian; 10% of patients had ha istory of chronic obstructive pulmonary disease or asthma; 34% had renal impairment; the International Staging System stage at study entry was I in 37%, II in 36%, and III in 25%; and 20% had high-risk chromosomal abnormalities. The median number of prior lines of therapy was three (range = 2–11). All patients had received a prior proteasome inhibitor and prior lenalidomide; 56% had received prior stem cell transplantation; 93% were refractory to lenalidomide; 76%, to a proteasome inhibitor; and 73%, to both an immunomodulator and a proteasome inhibitor.
The median progression-free survival was 11.53 months (95% confidence interval [CI] = 8.94–13.9 months) in the Isa-Pd group vs 6.47 months (95% CI = 4.47–8.28 months) in the Pd group (hazard ratio = 0.596, P = .0010). Overall response rates were 60.4% vs 35.3% (P < .0001).
How It Works
Isatuximab-irfc is an IgG1-derived monoclonal antibody that binds to CD38 expressed on the surface of hematopoietic and tumor cells, including multiple myeloma cells. Isatuximab-irfc induces apoptosis of tumor cells and activation of immune effector mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. Isatuximab-irfc inhibits the ADP-ribosyl cyclase activity of CD38. This agent can activate natural killer cells in the absence of CD38-positive target tumor cells and suppresses CD38-positive T-regulatory cells. The combination of isatuximab-irfc and pomalidomide enhanced ADCC activity and direct tumor cell killing compared with isatuximab-irfc alone in vitro and enhanced antitumor activity compared with activity of isatuximab-irfc or pomalidomide alone in a human multiple myeloma xenograft model.
How It Is Used
The recommended dose of isatuximab-irfc is 10 mg/kg via intravenous infusion in combination with pomalidomide and dexamethasone in 28-day cycles until disease progression or unacceptable toxicity. For cycle 1, doses are given on days 1, 8, 15, and 22; for cycle 2 and subsequent cycles, doses are given on days 1 and 15.
Isatuximab-irfc should be administered by a health-care professional with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions. Patients should be premedicated before isatuximab-irfc infusion. Product labeling provides specific instructions on premedication with dexamethasone, acetaminophen, H2 antagonists, and diphenhydramine.
No dose reductions of isatuximab-irfc are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of hematologic toxicity. For information concerning pomalidomide and dexamethasone used in combination with isatuximab-irfc, the manufacturer’s prescribing information for the agents should be consulted.
In the ICARIA-MM trial, the most common adverse events of any grade in the Isa-Pd group (≥ 20% of patients) were upper respiratory tract infection (57% vs 42% in the Pd group), infusion-related reactions (38% vs 0%), pneumonia (31% vs 23%), and diarrhea (26% vs 19%). The most common grade 3 or 4 adverse events included pneumonia, febrile neutropenia, and upper respiratory tract infection. Grade 3 or 4 hematologic laboratory abnormalities consisted of anemia in 32% vs 28%, neutropenia in 85% vs 69%, lymphopenia in 55% vs 43%, and thrombocytopenia in 30% vs 24%.
Serious adverse events occurred in 62% of patients receiving Isa-Pd, with the most common being pneumonia, upper respiratory tract infections, and febrile neutropenia. Adverse events led to dose interruption in 31% of patients, with the most common cause being infusion-related reaction. Adverse events led to permanent treatment discontinuation in 7% of patients; isatuximab-irfc alone was discontinued in 3% of patients due to infusion-related reactions. Fatal adverse events occurred in 11% of patients, with the most common being pneumonia and other infections.
Second primary malignancies were reported in 3.9% of patients in the Isa-Pd group vs 0.7% of the Pd group, with those in the Isa-Pd group consisting of squamous skin cell carcinoma, breast angiosarcoma, and myelodysplastic syndrome.
Isatuximab-irfc has warnings/precautions for infusion-related reactions; neutropenia; second primary malignancies; interference with laboratory tests, including serologic testing, serum protein electrophoresis, and immunofixation tests; and embryofetal toxicity.
Isatuximab-irfc should be permanently discontinued for grade ≥ 3 infusion-related reactions. Complete blood cell counts should be monitored periodically during treatment, and patients with neutropenia should be monitored for signs of infection. Patients should be monitored for development of second primary malignancies. For laboratory test interference, patients should be typed and screened prior to starting treatment, and blood banks should be informed that a patient has received the drug. It should be recognized that the agent may interfere with assays used to monitor M-protein, which may impact the determination of complete response.
Isatuximab-irfc is contraindicated in patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients. Patients should be advised not to breastfeed while receiving isatuximab-irfc.
1. U.S. Food and Drug Administration: FDA approves isatuximab-irfc for multiple myeloma. Available at www.fda.gov. Accessed April 2, 2020.
2. Sarclisa (isatuximab-irfc) injection for intravenous use prescribing information, sanofi-aventis U.S. LLC, March 2020. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2020/761113s000lbl.pdf. Accessed April 2, 2020.
3. Attal M, Richardson PG, Rajkumar SV, et al: Isatuximab plus pomalidomide and low-dose dexamethasone vs pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM). Lancet 394:2096-2107, 2019.