Multiple myeloma is a cancer that develops from plasma cells with abnormal genetic variations. Normally, plasma cells grow and divide to make new cells; once cells grow old or get damaged, they die. In contrast, due to the genetic variations in multiple myeloma, the myeloma cells replicate uncontrollably throughout the bone marrow, do not die quickly when old or damaged, crowd out normal blood cells in the bone marrow as they grow, and destroy the bone tissue. The antibodies synthesized by myeloma cells do not fight infections like normal antibodies do. Common signs and symptoms include anemia, bone pain, kidney damage due to elevated creatinine or serum protein, infection, fatigue, and hypercalcemia.
Like many types of malignancies, further treatment of multiple myeloma after relapsed, progressive, or refractory disease usually yields a shorter duration and lower quality of response compared to the initial response. There is a high demand for agents that treat multiple myeloma that do not respond or that progress after first- or subsequent-line therapy.
Isatuximab-irfc (Sarclisa, Sarclisa Escena) is a CD38-directed cytolytic antibody. CD38 is a glycoprotein expressed on the surface of hematopoietic cells (including lymphoid and myeloid cells) and tumor cells. When multiple myeloma is present, there is an overexpression of CD38 on malignant plasma cells. Isatuximab-irfc (Sarclisa, Sarclisa Escena) works by binding to CD38 and inducing apoptosis of tumor cells and activation of immune effector mechanisms including complement-dependent cytotoxicity (CDC) (causing tumor cell lysis and death), antibody-dependent cell-mediated cytotoxicity (ADCC) (causing tumor cell death by nonphagocytic processes via the activation of natural killer cells, macrophages, etc.), and antibody-dependent cellular phagocytosis (ADCP) by macrophages. The combination of isatuximab-irfc (Sarclisa, Sarclisa Escena) and pomalidomide enhanced ADCC activity and direct tumor cell killing compared to that of isatuximab-irfc (Sarclisa, Sarclisa Escena) alone in vitro, and the combination of isatuximab-irfc (Sarclisa, Sarclisa Escena) and pomalidomide also enhanced antitumor activity compared to the activity of isatuximab-irfc (Sarclisa, Sarclisa Escena) or pomalidomide alone in a human multiple myeloma xenograft model.
PEER-REVIEW LITERATURE FOR SARCLISA
IN COMBINATION WITH BORTEZOMIB, LENALIDOMIDE, AND DEXAMETHASONE, IN NEWLY DIAGNOSED MYELOMA INDIVIDUALS WHO ARE NOT ELIGIBLE FOR STEM CELL TRANSPLANTATION
The safety and efficacy of isatuximab-irfc (Sarclisa) in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) were evaluated in IMROZ (Facon et al., 2024), a multicenter, international, randomized (3:2), open-label, phase 3 study in 446 individuals with newly diagnosed multiple myeloma who are not eligible for stem cell transplantation. The median age was 72 years (range, 55–80). Individuals were randomly assigned to either Isa-VRd group or bortezomib, lenalidomide, and dexamethasone (VRd) group. Treatment was administered in both groups during four cycles of 42 days each for the induction period. After completion of cycle 4, individuals entered the continuous treatment period starting from cycle 5, in which 28-day cycles were administered up to disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). At a median follow-up of 59.7 months, the estimated PFS at 60 months was 63.2% in the isatuximab-VRd group and 45.2% in the VRd group (P<0.001). The improvement in PFS represented a 40% reduction in the risk of disease progression or death in individuals treated with Isa-VRd. The percentage of individuals with a complete response or better was statistically significantly higher in the Isa-VRd group compared to the VRd group (74.7% vs. 64.1%; P=0.01), as was the percentage of individuals with MRD-negative status and a complete response (55.5% vs. 40.9%; P=0.003). The incidence of serious adverse events was similar in the two groups.
IN COMBINATION WITH POMALIDOMIDE AND DEXAMETHASONE, AFTER RECEIVING AT LEAST TWO PRIOR THERAPIES INCLUDING LENALIDOMIDE AND A PROTEASOME INHIBITOR
The safety and efficacy of isatuximab-irfc (Sarclisa) were evaluated in ICARIA-MM (Attal et al., 2019), a multicenter, multinational, randomized (1:1), open-label, two-arm, phase 3 study in 307 adult individuals with relapsed and refractory multiple myeloma. Individuals had received at least two prior therapies including lenalidomide and a proteasome inhibitor (e.g., bortezomib [Velcade], carfilzomib [Kyprolis], ixazomib [Ninlaro]). The median number of prior lines of therapy was three (range, 2–11). All participants received a prior proteasome inhibitor, all participants received prior lenalidomide, and 56% of participants received prior stem cell transplantation; the majority of participants (93%) were refractory to lenalidomide, 76% to a proteasome inhibitor, and 73% to both an immunomodulator and a proteasome inhibitor. The median age was 67 years (range, 36–86). Participants received either isatuximab-irfc (Sarclisa) 10 mg/kg (as an intravenous infusion weekly in the first cycle and every 2 weeks thereafter) in combination with pomalidomide 4 mg and dexamethasone 40 mg (20 mg for individuals aged ≥75 years) (Isa-Pd, N=154) or pomalidomide 4 mg and dexamethasone 40 mg (Pd, N=153). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity, or consent withdrawal. The primary outcome of this study was PFS. At a median follow-up time of 11.6 months, the Isa-Pd group had a higher median PFS (11.5 vs 6.5 months; P=0.001) compared to the Pd group. PFS benefit with Isa-Pd occurred in the following prespecified subgroups: individuals with poor prognosis, aged 75 years or older, disease refractory to lenalidomide, a proteasome inhibitor, both lenalidomide and a proteasome inhibitor, or to lenalidomide at the last line prior to study entry. The median duration of treatment was 41 weeks for the Isa-Pd group compared to 24 weeks for the Pd group. There was a high number of participants who discontinued treatment: 87 of 152 individuals in the Isa-Pd group and 114 of 149 individuals in the Pd group, although all 307 individuals were included in the intention-to-treat analysis. The most frequent treatment-emergent adverse events (any grade) were infusion reactions, upper respiratory tract infections, and diarrhea.
IN COMBINATION WITH CARFILZOMIB AND DEXAMETHASONE, AFTER RECEIVING ONE TO THREE PRIOR LINES OF THERAPY
The safety and efficacy of isatuximab-irfc (Sarclisa) were evaluated in IKEMA (Moreau et al., 2020), a multicenter, multinational, randomized (3:2), open-label, two-arm, phase 3 study in 302 adult individuals with relapsed and/or refractory multiple myeloma. Individuals had received one to three prior therapies: proteasome inhibitors (90%), immunomodulators (78%, including 43% who received lenalidomide), and 61% received prior stem cell transplantation. Refractory therapies included proteasome inhibitors (33%), immunomodulators (45%, including 33% refractory to lenalidomide), and 21% were refractory to both a proteasome inhibitor and an immunomodulator.
The median number of prior lines of therapy was two (range, 1–4). The median age was 64 years (range, 33–90). Participants received either isatuximab-irfc (Sarclisa) 10 mg/kg (as an intravenous infusion weekly in the first cycle and every 2 weeks thereafter) in combination with carfilzomib and dexamethasone (Isa-Kd, N=179) or carfilzomib and dexamethasone (Kd, N=123). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. The primary outcome of this study was PFS. The result was a 45% reduction in the risk of disease progression or death in those treated with Isa-Kd compared to Kd.
PEER-REVIEW LITERATURE FOR SARCLISA ESCENA
IN COMBINATION WITH BORTEXOMIB, LENALIDOMIDE, AND DEXAMETHASONE, IN NEWLY DIAGNOSED MULTIPLE MYELOMA INDIVIDUALS WHO ARE NOT ELIGIBLE FOR STEM CELL TRANSPLANTATION
ISASOCUT is a multicenter, open-label, single-arm, investigator-sponsored phase 2 clinical study in 74 adults with newly diagnosed multiple myeloma who are not eligible for stem cell transplantation that evaluated the safety and efficacy of isatuximab-irfc (Sarclisa Escena) administered subcutaneously in combination with bortezomib, lenalidomide, and dexamethasone (Sarclisa Escena-VRd) during 12 cycles of 28-days for the induction period. Individuals entered the continuous treatment period starting from cycle 13 and received isatuximab-irfc (Sarclisa Escena) in combination with lenalidomide in 28-day cycles administered up to disease progression or unacceptable toxicity. The primary objective is rate of very good partial response (VGPR) or better, according to the 2016 IMWG criteria assessed by IRC. At data cutoff (January 13, 2025), the rate of individuals who had VGPR or better at 8 months was 87.8% (n=65) [95% CI, 78-94].
IN COMBINATION WITH POMALIDOMIDE AND DEXAMETHASONE, AFTER RECEIVING AT LEAST ONE PRIOR THERAPY INCLUDING LENALIDOMIDE AND A PROTEASOME INHIBITOR
IRAKLIA is a multicenter, multinational, randomized (1:1) open-label, 2-arm, phase 3 study in 531 adults with relapsed and/or refractory multiple myeloma that evaluated the safety and efficacy of isatuximab-irfc (Sarclisa Escena) 1400 mg fixed dose administered subcutaneously with On-Body Delivery System (OBDS) device in combination with pomalidomide and dexamethasone (Sarclisa Escena-Pd) or isatuximab-irfc (Sarlisa) as a 10 mg/kg intravenous infusion in combination with pomalidomide and dexamethasone. Treatment was administered in both arms in 28-day cycles until disease progression or unacceptable toxicity. The coprimary endpoints were overall response rate (ORR) and the pharmacokinetic endpoint of Ctrough at steady state (corresponding to predose at Cycle 6 Day 1). The results show that subcutaneous isatuximab-irfc (Sarclisa Escena) in combination with Pd is non-inferior to intravenous isatuximab-irfc (Sarclisa) in combination with Pd in terms of ORR (71.1% vs 70.5%) after a median follow-up of 12 months, and Ctrough at steady state. Overall safety was similar between both arms.
IN COMBINATION WITH CARFILZOMIB AND DEXAMETHASONE, AFTER RECEIVING ONE TO THREE PRIOR LINES OF THERAPY
IZALCO is a two-part, randomized, open-label phase 2 study evaluating the efficacy and safety of subcutaneous (SC) isatuximab-irfc (Sarclisa Escena) in combination with carfilzomib and dexamethasone (Kd), for the treatment of 74 adults with relapsed and/or refractory multiple myeloma who have received one to three prior lines of therapy. The study compared two SC administration methods: Manual SC injection and On-body injector (OBI) device. In Part 1, isatuximab-irfc (Sarclisa Escena) was injected SC manually (cycles 1−6) into eight individuals over 6 to 8 minutes. In Part 2, individuals were randomly assigned to isatuximab-irfc (Sarclisa Escena) SC by manual injection (cycles 1−3) followed by OBI administration (cycles 4−6) or to isatuximab-irfc (Sarclisa Escena) OBI (cycles 1−3) followed by manual injection (cycles 4−6). From cycle 7, all individuals in Parts 1 and 2 could choose either treatment method. The primary endpoint of ORR was achieved, with a response rate of 79.7% at a median follow-up of 10.1 months. The majority of individuals (74.5%) preferred the OBI, supporting its use as a convenient SC delivery method. Additionally, the safety and pharmacokinetics were comparable between administration via on-body injector and manual injection.
OFF-LABEL INDICATION
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
