Isatuximab Combination Significantly Sustains MRD Negativity in NDMM

“Isa-KRd significantly increased the rate of 10–6 1-year sustained MRD negativity, as compared with KRd, even among high-risk and very high-risk patients,” according to study author Francesca Gay, MD, PhD.

Combining isatuximab-irfc (Sarclisa) with carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Isa-KRd) significantly increased the rate of sustained minimal residual disease (MRD)–negative status compared with KRd alone among patients with newly diagnosed multiple myeloma (NDMM), according to data from the phase 3 IsKia trial (NCT04483739) presented at the 2025 European Hematology Association Congress.1

At a threshold of 10–5 after full-dose consolidation in the Isa-KRd (n = 151) and KRd (n = 151) arms, respectively, the MRD-negative rates were 77% vs 67% after full-dose consolidation (OR, 1.67; P = .049) and 79% vs 74% after light consolidation. At a threshold of 10–6, the respective MRD-negative rates in each arm were 68% vs 48% after full-dose consolidation and 74% vs 64% after light consolidation (OR, 1.63; P = .055).

MRD-negative status was sustained for 1 year in 66% of the Isa-KRd arm and 59% of the KRd arm at a threshold of 10–5; these rates were 52% vs 38% at a threshold of 10–6 (OR, 1.82; P = .012). Treatment with Isa-KRd improved 1-year sustained MRD negativity vs KRd across patient subgroups at a cut-off of 10–6, which included those with high-risk disease (44% vs 31%; OR, 1.74), 2 or more high-risk cytogenetic abnormalities (62% vs 20%; OR, 6.30), and second revision of the International Staging System (R2-ISS) stage III or IV disease (47% vs 35%; OR, 1.73).

Investigators noted functional high-risk status, defined as progressive disease before 18 months from randomization, in 3% of patients who received Isa-KRd and 4% of those who received KRd. Additionally, 6% of patients from both arms had functional high-risk status and/or pre-progression or deaths.

“Isa-KRd significantly increased the rate of 10–6 1-year sustained MRD negativity, as compared with KRd, even among high-risk and very high-risk patients,” Francesca Gay, MD, PhD, an associate professor in the University of Torino Department of Molecular Biotechnology and Health Sciences, and a hematologist at the Division of Hematology and SSD Clinical trials in onco-hematology and multiple myeloma at Azienda Ospedaliero-Universitaria Città della Salute e della Scienza in Torino, Italy, stated in the presentation.1 “The rate of early relapse was low in both arms, supporting the effectiveness of the second-generation [proteasome inhibitor] carfilzomib in this setting….When comparing highly effective regimens, the 10–6 MRD negativity cut-off was more informative than the 10–5 MRD negativity cut-off.”

Across 42 active sites in the IsKia trial, patients 70 years or younger with transplant-eligible NDMM were randomly assigned to receive induction therapy with Isa-KRd or KRd alone in four 28-day cycles. Treatment included isatuximab at 10 mg/mg intravenously on days 1, 8, 15, and 22 of cycle 1 followed by 10 mg/kg on days 1 and 15 of cycles 2 to 4; carfilzomib at 20 mg/m2 on day 1 of cycle 1 followed by 56 mg/m2 on days 8 and 15 of cycle 1 and days 1, 8, and 15 of cycles 2 to 4; lenalidomide at 25 mg daily on days 1 to 21; and dexamethasone at 40 mg on days 1, 8, 15, and 22.

Following induction therapy, patients underwent mobilization with cyclophosphamide at 2 to 3 g/m2 followed by G-CSF for stem cell collection and melphalan at 200 mg/m2 plus autologous stem cell transplantation. Additionally, patients underwent post-ASCT full-dose consolidation therapy with Isa-KRd or KRd alone for four 28-cycles followed by light consolidation therapy in twelve 28-day cycles.

The trial’s primary end point was the rate of MRD negativity following ASCT consolidation therapy per next-generation sequencing (NGS).2 Secondary end points included post-induction MRD negativity per NGS, progression-free survival, overall response rate, duration of response, overall survival, and safety.

At the time of light consolidation therapy in the Isa-KRd (n = 126) and KRd arms (n = 136), the median age was 61 years (IQR, 54-66) compared with 60 years (IQR, 54-64), and most patients were male (54% vs 56%). Additionally, most patients in each arm had standard cytogenetic risk (85% vs 83%), 0 high-risk cytogenetic abnormalities (56% vs 54%), R-ISS stage II disease (59% vs 58%), and R2-ISS stage II (35% vs 34%) or stage III disease (34% vs 36%).

Grade 1/2 hematologic toxicities in the Isa-KRd arm and KRd arm included anemia (6% vs 6%), neutropenia (9% vs 7%), and thrombocytopenia (8% vs 11%); grade 3 neutropenia affected 17% and 15% of patients in each arm. Regarding non-hematologic toxicities, the most common grade 1/2 events in each arm included COVID-19 (20% vs 24%), respiratory tract infection (21% vs 10%), diarrhea (18% vs 14%), and asthenia or fatigue (12% vs 12%).

Patients in the Isa-KRd arm discontinued therapy due to grade 3 nausea (n = 1), grade 3 cytomegalovirus chorioretinitis (n = 1), grade 3 dyspnea (n = 1), and grade 3 mood changes (n = 1). Additionally, those in the KRd arm discontinued treatment due to grade 4 myelodysplastic syndrome with multilineage dysplasia (n = 1), grade 3 hepatitis B reactivation (n = 1), and grade 2 decreased appetite (n = 1).

Two patients in the Isa-KRd arm died due to pulmonary embolism (n = 1) and ischemic cerebral infarction (n = 1). Additionally, 1 patient in the KRd arm died due to cardiac arrest with an unknown cause at home.

References

1. Broijl A, Roeloffzen W, Dimopoulos MA, et al. Analysis of sustained MRD negativity in patients with newly diagnosed multiple myeloma treated with carfilzomib-lenalidomide-dexamethasone with or without Isatuximab (phase III IsKia trial). Presented at: European Hematology Association 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract S208.
2. Isa-KRd vs KRd in newly diagnosed multiple myeloma patients eligible for autologous stem cell transplantation (IsKia TRIAL) (IsKia). ClinicalTrials.gov. Updated February 26, 2025. Accessed June 16, 2025. https://tinyurl.com/5c86ztax