The first MRD data from the phase 3 EXCALIBER-RRMM trial support iberdomide-based triplet therapy as early as first relapse, with PFS follow-up ongoing.
Iberdomide (Zenbexus) plus daratumumab and hyaluronidase-fihj (Darzalex Faspro) and dexamethasone (IberDd) significantly improved the rate of minimal residual disease (MRD)–negative complete response (CR) at any time vs daratumumab, bortezomib (Velcade), and dexamethasone (DVd) in patients with relapsed/refractory multiple myeloma who had received 1 or 2 prior lines of therapy, according to findings from the phase 3 EXCALIBER-RRMM trial (NCT04975997) presented at the
At a median follow-up of 15.7 months, the MRD-negative CR rate at any time was 41.1% (n = 85) in the IberDd arm (n = 207) vs 20.7% (n = 44) in the DVd arm (n = 213), for a proportion difference of 20.1% (95% CI, 11.5%-28.6%; P < .0001) and an odds ratio of 2.75 (95% CI, 1.77-4.30). These data formed the basis of the
"This really is a watershed moment for us in the field to be able to have an alternative end point that [will] offer access to patients sooner," said lead study author Sagar Lonial, MD, FACP, FASCO, of Winship Cancer Institute of Emory University in Atlanta, Georgia, in the presentation.1
EXCALIBER-RRMM is the first randomized phase 3 trial in relapsed/refractory multiple myeloma to use dual primary end points of MRD-negative CR and progression-free survival (PFS). Per agreement with the FDA, MRD data were withheld until MRD-based approval or the PFS interim analysis to preserve the integrity of the PFS end point.
The trial enrolled adults who had received 1 or 2 prior lines of therapy, had progressive disease, and were not refractory to anti-CD38 monoclonal antibodies. In stage 1, which followed FDA Project Optimus principles, 279 patients were randomly assigned 1:1:1:1 to IberDd with iberdomide at 1.0 mg (n = 70), 1.3 mg (n = 70), or 1.6 mg (n = 69), or to DVd (n = 70). The 1.0-mg dose was selected for stage 2, in which 660 patients were randomly assigned 1:1 to IberDd or DVd; the full confirmatory analysis group for PFS will include 800 patients.
In the IberDd arm, iberdomide was given orally once daily on days 1 through 21 of each 28-day cycle, with subcutaneous daratumumab at 1800 mg and dexamethasone at 40 mg or 20 mg. The MRD analysis included the first 420 randomly assigned patients and was powered to detect a 15% absolute improvement in MRD-negative CR (approximately 85% power; 1-sided α of 0.005). MRD was assessed by next-generation flow at a sensitivity of 10⁻⁵.
Baseline characteristics were balanced. The median age was 68 years (range, 37-85) in the IberDd arm and 67 years (range, 35-87) in the DVd arm. Most patients had prior exposure to immunomodulatory drugs (89.9% vs 90.6%), 44.4% vs 42.7% had lenalidomide-refractory disease, and 50.2% vs 47.4% had expanded high-risk cytogenetics.
The overall response rate was 88.9% with IberDd vs 76.1% with DVd, and the rate of CR or better was 45.9% vs 24.9%, respectively. The rates of very good partial response or better were 74.4% vs 61.5%, and the stringent CR rates were 29.5% vs 11.3%.
Across subgroups, MRD-negative CR rates favored IberDd in patients with expanded high-risk cytogenetics (n = 205; 33.7% vs 21.8%), lenalidomide-refractory disease (n = 183; 33.9% vs 22.1%), and lenalidomide-refractory disease in the last prior line of therapy (n = 173; 36.7% vs 24.1%), as well as in patients aged 75 years or older.
At data cutoff, 62.3% of patients in the IberDd arm remained on treatment vs 46.0% in the DVd arm. The median duration of treatment was 14.8 months (range, 0.5-32.9) vs 13.0 months (range, 0.5-32.6), and the median relative dose intensity of iberdomide was 90.5%.
In the safety population (n = 204 per arm), grade 3/4 treatment-emergent adverse effects (TEAEs) occurred in 91.7% of patients in the IberDd arm vs 70.1% in the DVd arm. Neutropenia, an on-target effect of iberdomide, was the most common grade 3/4 AE (84.3% vs 11.3%), and febrile neutropenia occurred in 5.4% vs 0.5%. Grade 3/4 neutropenia was most frequent in cycles 1 and 2 and declined thereafter. Overall, 82.4% of patients in the IberDd arm received granulocyte colony-stimulating factor; among patients with iberdomide modifications because of neutropenia, 51.5% had dose interruptions, 13.2% had dose reductions, and 1.0% (n = 2) discontinued.
Grade 3/4 thrombocytopenia (12.7% vs 44.1%) and any-grade peripheral sensory neuropathy (12.3% vs 42.6%) were less frequent with IberDd. Grade 3 infections occurred in 35.8% vs 21.1% of patients and grade 4 infections in 3.4% vs 0.5%, most commonly pneumonia; fatal infections occurred in 2.0% vs 1.5%. Hypogammaglobulinemia was reported in 16.7% vs 10.3%, and 27.9% vs 13.7% of patients received immunoglobulin replacement therapy. Venous thromboembolism occurred in 5.9% vs 3.9%, with no grade 3/4 events in the IberDd arm.
Discontinuations due to AEs occurred in 8.7% vs 3.3% of patients. Deaths were reported in 11.1% vs 15.5%, primarily due to disease progression; grade 5 TEAEs occurred in 5.4% vs 2.5%, of which 1.5% vs 1.0% were considered treatment related.
Evaluation of the PFS dual primary end point is ongoing. Iberdomide is also being evaluated as maintenance therapy vs lenalidomide in the phase 3 EXCALIBER-Maintenance trial (NCT05827016), and the CELMoD mezigdomide is under investigation with proteasome inhibitors in the phase 3 SUCCESSOR-1 (NCT05519085) and SUCCESSOR-2 (NCT05552976) trials, with a Prescription Drug User Fee Act date of May 13, 2027, for mezigdomide plus carfilzomib (Kyprolis) and dexamethasone. The investigators concluded that IberDd is a new standard of care for relapsed/refractory multiple myeloma that can be used as early as first relapse across diverse clinical settings, including community practice.
