Iberdomide Combo Leads to Deepening Responses in Transplant-Ineligible NDMM

At the 22nd Annual International Myeloma Society Meeting and Exposition, results from cohort 2 of the phase 2 GEM-IBERDARAX trial (NCT05527340) revealed that iberdomide (CC-220), daratumumab (Darzalex), and dexamethasone elicited deep responses in patients with transplant-ineligible newly diagnosed multiple myeloma who are mostly frail.¹

Among efficacy-evaluable patients (n = 73), at a median follow-up of 11.1 months (range, 3.5-29.2) and a data cutoff of June 15, 2025, the overall response rate (ORR) was 93.1%. 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 (SD; 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 Cetner-IBMCC (USAL-CSIC) in Spain.

What Are the Prior Data With Daratumumab-Based Regimens in Newly Diagnosed Multiple Myeloma?

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 CELMoD that has shown immunomodulatory activity and early efficacy signals when combined with other antimyeloma agents. In the GEM-IBERDERAX trial, 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.

What Was the Design of Cohort 2 of GEM-IBERDARAX?

GEM-IBERDARAX enrolled patients at least 18 years of age 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 IFMs frailty score.

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, and on day 1 of cycle 7 and onward; and dexamethasone orally at 40 mg (20 mg if older than 75 years of age) 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 to cohort 2. After all 77 patients had completed 6 cycles of therapy, 21 patients had discontinued due to death (n = 7), physician decision (n = 5), patient withdrawal (n = 4), adverse effects (AEs; n = 3), and disease progression (n = 2).

What Were the Baseline Characteristics of Patients in Cohort 2 of GEM-IBERDARAX?

Patients had a median age of 77 years (range, 67-88), and 54.5% of patients were at least 75 years of age. ECOG performance statuses included 0 (27.3%), 1 (54.5%), and 2 (14.3%). Most patients enrolled in cohort 2 were frail (68.9%) or ultrafrail (40.5%). Additionally, 28.6% of patients had International Staging System III disease, and 30.4% of patients had high-risk cytogenetic abnormalities.

What Were Additional Efficacy Outcomes FromGEM-IBERDARAX?

Response outcomes after each of the first 6 cycles of therapy were as follows:

• Cycle 1: ORR, 71.2%; best responses: VGPR (16.4%), PR (54.8%), and SD (28.8%)
• Cycle 2: ORR, 83.6%; best responses: VGPR (35.6%), PR (47.9%), and SD (16.4%)
• Cycle 3: ORR, 89.0%; best responses: VGPR (63.0%), PR (26.0%), and SD (11.0%)
• Cycle 4: ORR, 90.4%; best responses: CR (1.4%), VGPR (65.8%), PR (23.3%), and SD (9.6%)
• Cycle 5: ORR, 90.4%; best responses: sCR (2.7%), CR (2.7%), VGPR (68.5%), PR (16.4%), SD (8.2%), and progressive disease (PD; 1.5%)
• Cycle 6: ORR, 91.8%; best responses: sCR (16.4%), CR (4.1%), VGPR (54.8%), PR (16.4%), SD (6.8%), and PD (1.5%)

Responses deepened over time. The median time to best response was 5 cycles (range, 1-11).

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%. Three patients experienced disease progression; 5 died due to infections (n = 5), PD (n = 2), bleeding (n = 2), sudden death (n = 1), epileptic status (n = 1), and prostate cancer (n = 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 patients deemed frail, 3 progressed and 10 died; all 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.

What Was the Safety Profile of Iberdomide Plus Daratumumab and Dexamethasone in Patients With Transplant-Ineligible, Newly Diagnosed Multiple Myeloma?

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%) like 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; these toxicities included pneumonia (2.6%) and febrile neutropenia (1.3%). Overall, 73% of patients were still receiving treatment as of the data cutoff.

“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.

Disclosures: González-Calle reported receiving honoraria from GSK and Johnson & Johnson; participating in advisory board meetings with GSK and Johnson & Johnson; receiving research support from GSK and Pfizer; and receiving travel support from Sanofi, GSK, and Johnson & Johnson.

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.