FDA Approval of Iberdomide Marks Historic Milestone in Multiple Myeloma

The FDA's accelerated approval of iberdomide as a combination therapy marks the first approval of a cereblon E3 ligase modulator (CELMoD) for relapsed/refractory multiple myeloma. It is also the first myeloma approval based on measurable residual disease (MRD) data rather than traditional endpoints such as progression-free survival or overall survival.

Based on interim MRD results from the phase 3 EXCALIBER-RRMM trial, iberdomide is now approved in combination with daratumumab and hyaluronidase-fihj and dexamethasone (IberDd) for adults with multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent. "This combination therapy has shown really deep responses, including in patients who are refractory to pomalidomide or lenalidomide," says Faiz Anwer, MD, a hematologist/oncologist and Professor of Medicine at Cleveland Clinic Cancer Institute, who served as the Cleveland Clinic principal investigator on the phase 3 trial as well as the phase 1/2 CC-220-MM-001 trial that preceded it.

Immunomodulatory (IMiD) drugs like pomalidomide and lenalidomide bind to the cellular protein cereblon, which essentially acts as the body's internal trash disposal system by identifying damaged proteins for destruction. However, over time, myeloma cells can downregulate or mutate cereblon, preventing the drug from attaching to it.

A successor to IMiDs, iberdomide binds cereblon about 20 times more tightly than lenalidomide or pomalidomide, trapping and breaking down Ikaros and Aiolos proteins, which myeloma cells rely on to survive. Simultaneously, the oral medication stimulates the immune system's T-cells to stave off disease. The increased potency of this medication allows for a much lower dose than older agents (1mg once daily, compared with typical 25mg for lenalidomide and 4mg for pomalidomide).

Study design

The phase 1/2 trial evaluated iberdomide and dexamethasone in 197 patients across 42 cancer centers who had received a median of five (dose escalation) to six (dose expansion) prior lines of therapy. The study demonstrated meaningful clinical activity in heavy pretreated patients, including those who were refractory to IMiDs, with overall response rates of 32% and 26% in the dose-escalation and dose-expansion cohorts, respectively.

Building on this study, the two-stage, randomized, open-label phase 3 EXCALIBER-RRMM trial was designed to select the iberdomide dose (stage 1) and then compare IbeDd with DVd (stage 2) in adults who had received one or two lines of previous therapy and had progressive disease. The research encompassed patients at 211 hospitals and community-based sites in 31 countries. Patients with anti-CD38-refractory or bortezomib-refractory disease were excluded. Patients were randomized to receive IberDd or daratumumab, bortezomib and dexamethasone (DVd).

During stage 1 of the trial, researchers identified 1mg as the appropriate iberdomide dose, chosen from three doses tested (1.0, 1.3 and 1.6mg) in 279 patients. During stage 2 of the trial, 660 patients were randomized, for a total of 939 patients across both stages. The dual primary endpoints were MRD-negative complete response at any time and progression-free survival. The secondary endpoints included overall survival, response rates, duration of response and safety.

Study outcomes

The IbeDd regimen nearly doubled MRD-negative complete response rates compared to DVd (41% vs. 21%; odds ratio 2.8, 95% CI 1.8 to 4.3; P<0.0001) in the first 420 randomized patients. The data were published in Lancet Oncology.

Using MRD-negative complete response as an intermediate endpoint allowed for accelerated drug approval without having to wait years for the data to mature. Continued approval depends on confirmation of clinical benefit in the ongoing progression-free survival analysis, which is the trial’s second dual primary endpoint. "MRD negativity indicates the patient is in deep remission," explains Dr. Anwer. "This test, when done serially, gives us early signals that should translate into longer progression-fee survival and overall survival improvement, which we continue to monitor."

The approval covers patients as early as first relapse, but Dr. Anwer notes that many patients may benefit from the iberdomide regimen in later lines of therapy as well, including after relapse from bispecific antibody or CAR T-cell therapy.

In terms of side effects, 92% of patients in the IberDd arm and 70% of patients in the DVd arm experienced grade 3 or 4 adverse events. Grade 3 or 4 neutropenia occurred in 84% vs. 11% and infection in 39% vs. 22%. Pneumonia was the most common adverse event (18% vs. 6%).

The FDA label carries a boxed warning for embryo-fetal toxicity and serious venous and arterial thromboembolism. The drug is available only through the Zenbexus REMS program.

Dr. Anwer cautions that since the risk of infection is high, close monitoring for neutropenia and infection is warranted, along with growth factor support and dose modifications as needed.

Patients with an eGFR below 30 mL/min or on dialysis were excluded from the trial, but the MRD-negative complete response rate favored iberdomide in every renal function subgroup, including 36% vs. 8% in patients with renal function below 45 mL/min (38 patients). The label recommends a reduced dose of 0.75mg daily when eGFR is below 30 mL/min/1.73 m² in patients not on dialysis, and no adjustment for higher eGFR or intermittent hemodialysis.

What's next?

Cleveland Clinic Cancer Institute is involved in ongoing studies of CELMoDs in numerous combinations as well as studying its use in the autologous transplant setting.