Iberdomide Triplet Regimen Signals Deep Responses in Multiple Myeloma

Over time, the triplet regimen of iberdomide (CC-220), daratumumab (Darzalex), and dexamethasone has led to deepening responses in newly diagnosed, transplant-ineligible patients with multiple myeloma, according to results of the phase 2 GEM-IBERDARAX trial (NCT05527340) presented at the 22nd Annual International Myeloma Society Meeting and Exposition in September.¹

Among efficacy-evaluable patients (n = 73) from cohort 2 of the study, the overall response rate (ORR) was 93.1% at a median follow-up of 11.1 months (range, 3.5-29.2) at a data cutoff of June 15, 2025. Best responses included stringent complete response (sCR; 30.1%), CR (4.1%), very good partial response (VGPR; 49.3%), PR (9.6%), and stable disease (6.8%).

“Importantly, most patients were frail or ultrafrail, and the safety profile was acceptable and manageable,” lead study author Verónica González-Calle, MD, PhD, said during the presentation.

González-Calle is a consultant in the Hematology Department at the University Hospital of Salamanca/IBSAL/Cancer Research Center-IBMCC (USAL-CSIC) in Spain.

Daratumumab plus lenalidomide (Revlimid) and dexamethasone is the current standard of care for older patients with transplant-ineligible, newly diagnosed multiple myeloma, particularly for frail patients. Iberdomide is an oral, novel cereblon E3 ligase modulatory drug that has shown immunomodulatory activity and early efficacy signals when combined with other antimyeloma agents. In the GEM-IBERDARAX trial, researchers from the Spanish Myeloma Group investigated iberdomide plus dexamethasone alone (cohort 1) or in combination with daratumumab (cohort 2) in transplant-ineligible patients with newly diagnosed multiple myeloma. The findings from cohort 1 have been previously reported.

Patients in cohort 2 received iberdomide orally at 1.6 mg on days 1 through 21; this dose was later reduced to 1 mg following protocol amendment. Patients also received daratumumab subcutaneously at 1800 mg on days 8, 15, and 22 of cycles 1 and 2; on days 1 and 15 of cycles 3 through 6; on day 1 of cycle 7 and onward; and dexamethasone orally at 40 mg (20 mg if older than 75 years) on days 1, 8, 15, and 22 every 4 weeks. Patients were treated until disease progression, unacceptable toxicity, or study withdrawal.

ORR and CR rate served as the primary end points. Secondary end points included safety, minimal residual disease (MRD), progression-free survival (PFS), and overall survival (OS).

Between October 2022 and February 2025, 129 patients were assessed for eligibility, 77 of whom were enrolled in cohort 2. Those 77 patients completed 6 cycles of therapy; 21 then discontinued due to death (n = 7), physician decision (n = 5), patient withdrawal (n = 4), adverse events (AEs; n = 3), or disease progression (n = 2).

Baseline Characteristics of Patients in Cohort 2

GEM-IBERDARAX enrolled patients 18 years and older with a confirmed diagnosis of multiple myeloma who were ineligible for autologous stem cell transplant due to age, comorbidities, or frailty. Patients needed to have an ECOG performance status of 0 to 2. The trial also required that at least 30% of patients meet frailty criteria per the Intergroupe Francophone du Myélome frailty score.

Patients had a median age of 77 years (range, 67-88), and 54.5% were 75 years or older. ECOG performance statuses included 0, 1, and 2.Most patients enrolled in cohort 2 were frail (68.9%); of those 40.5% were ultrafrail. Additionally, 28.6% of patients had International Staging System III disease, and 30.4% had high-risk cytogenetic abnormalities.

After 6 cycles of iberdomide plus daratumumab and dexamethasone, the MRD negativity rate in the efficacy-evaluable population was 27.4%. This rate was 34.5% among patients with a best response of VGPR or better (n = 55) and 73.3% among those with a best response of CR or better (n = 15).

The 12-month PFS rate was 80.8%, and the 12-month OS rate was 81.1%.

“These results are encouraging considering this frail population enrolled, and the relatively short follow-up,” González-Calle noted.

When survival outcomes were stratified by frailty status, among the 23 patients deemed fit, none progressed, and 2 died; the 12-month PFS and OS rates were 86.5% and 86.5%, respectively. Among the 51 frail patients, 3 progressed and 10 died; all 13 were ultrafrail. The 12-month PFS and OS rates in this population were 77.4% and 81.7%, respectively.

“These results highlight the prognostic impact of frailty in this setting,” González-Calle added.

Safety and Toxicities

Across all enrolled patients, the most common any-grade and grade 3 or higher AEs were neutropenia (74%; 67.5%), including febrile neutropenia (5.2%; 5.2%); anemia (20.8%; 5.2%); thrombocytopenia (18.2%; 6.5%); gastrointestinal AEs (32.5%; 2.6%), including diarrhea (16.9%; 1.3%) and constipation (15.6%; 0%); skin toxicities (32.5%; 2.6%), including rash (23.4%; 2.6%) and other toxicities such as edema and pruritus (9.1%; 0%); fatigue (16.9%; 3.9%); and nausea (6.5%; 0%). Additionally, any-grade and grade 3 or higher infections occurred at rates of 48.1% and 16.9%, respectively, and included respiratory infections (39%; 9.1%) such as pneumonia (5.2%; 3.9%) and COVID-19 (7.8%; 1.3%); urinary infection (11.7%; 1.3%); gastroenteritis (2.6%; 0%); and other infections (11.7%; 6.5%).

In cohort 2, during the first 6 cycles, patients received initial doses of iberdomide at 1.6 mg (71.4%), 1.3 mg (1.4%), and 1 mg (27.2%). Iberdomide dose reductions due to toxicities occurred in 36.4% of patients; these toxicities included neutropenia (50.5%), fatigue (17.9%), rash (17.9%), and infections (10.7%). Iberdomide discontinuations due to toxicities occurred in 3.9% of patients: pneumonia (2.6%) and febrile neutropenia (1.3%). As of the data cutoff, 73% of patients were still receiving treatment.

“The study is ongoing, and longer follow-up will confirm the sustained efficacy and monitor long-term safety in this challenging population,” González-Calle concluded.

Reference

González-Calle V, Rosiñol L, Puig N, et al. Efficacy and safety of iberdomide, daratumumab, and dexamethasone, in transplant-ineligible NDMM patients: initial analysis of the GEM-IBERDARAX trial. Presented at: 22nd International Myeloma Society Annual Meeting; September 17-20, 2025, Toronto, Canada. Abstract OA-63.