Iberdomide: A New Immunomodulatory Drug for Heavily Refractory Myeloma

One-third of patients with relapsed/refractory multiple myeloma (MM) responded to treatment with the investigational agent iberdomide, according to early results from a first-in-human trial. Sagar Lonial, MD, from the Winship Cancer Institute of Emory University in Atlanta, who reported these findings at the 2019 American Society of Clinical Oncology annual meeting, added that the drug’s safety profile was as expected for a patient population with such heavily refractory disease.

This phase Ib/IIa, open-label, multicenter, dose-escalation study is the first clinical trial of iberdomide, a cereblon E3 ligase immunomodulatory drug (IMID) that has demonstrated “enhanced tumoricidal and immune stimulatory effects in preclinical studies,” Dr. Lonial explained.

Sixty-six patients (median age = 65 years; range = 33-79 years) received treatment with iberdomide and dexamethasone. Eligible participants had relapsed/refractory MM and progressive disease on or within 60 days of last MM therapy.

Patients had received a median of five prior lines of therapy (range = 2-12), and the median time from diagnosis of MM to study enrollment was 7.2 years (range = 2.8-20.1 years). This patient population had heavily refractory disease, Dr. Lonial commented. “Almost three-quarters were either lenalidomide- or IMID-refractory, two-thirds were proteasome inhibitor–refractory, and another 71% were anti-CD38 monoclonal antibody–refractory.”

Per study protocol, iberdomide was administered in escalating doses (ranging from 0.3 to 1.3 mg) on days 1 through 21 of each 28-day treatment cycle; dexamethasone 40 mg (20 mg in patients >75 years) was administered on days 1, 8, 15, and 22 of each cycle.

As of April 15, 2019 (data cutoff), 20 patients (30.3%) were still receiving treatment. The most common reasons for treatment discontinuation were progressive disease (n=38; 57.6%) and adverse events (AEs; n=6; 9.1%). The remaining two patients discontinued based on physician decision or for other reasons.

The most common treatment-related AEs of any grade were hematologic, which Dr. Lonial noted was common in this class of drugs:

  • anemia (n=24; 36.4%)
  • neutropenia (n=22; 33.3%)
  • thrombocytopenia (n=9; 13.6%)

He added that AEs occurred infrequently in the first cycle of treatment, but included grade 3/4 anemia (n=10; 15.2%), infection (n=7; 10.6%), and neutropenia (n=6; 9.1%). “Many of the IMID-related side effects were simply not seen in grade 3 or grade 4 during the first cycle,” he said. “This speaks to the tolerance of this agent, particularly compared with lenalidomide and pomalidomide, where it is [common] to see side effects within that first cycle.”

Two dose-limiting toxicities (grade 4 sepsis and grade 3 pneumonia) were observed at the 1.2-mg and 1.3-mg dose levels, but the researchers noted that the maximum tolerated dose and recommended phase II dose has not yet been reached.

Fifty-nine patients were evaluable for efficacy. The overall response rate (ORR; including partial responses [PRs] or better) was 32.2% (n=19). This included: two very good PR and 17 PRs. Twenty-one patients experienced stable disease, while nine had disease progression while on treatment.

Dr. Lonial noted that responses were seen across difficult-to-treat subgroups, such as patients with disease that was refractory to IMIDs (ORR=35.3%) or daratumumab and pomalidomide (ORR=29.6%). “This IMID was able to overcome drug resistance to lenalidomide and pomalidomide,” he concluded.

Findings from this ongoing first-in-human study are limited by the small patient population and the trial’s open-label design. Dr. Lonial and colleagues noted that, although promising, the clinical activity of this new agent needs to be confirmed in larger studies with longer follow-up. Iberdomide also is being evaluated in combination with different agents, including daratumumab and bortezomib.

The authors report relationships with Celgene, which sponsored the trial.

Reference

Lonial S, van de Bonk NWCJ, Popat R, et al. First clinical (phase 1b/2a) study of iberdomide (CC-220; IBER), a CELMoD, in combination with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Abstract #8006. Presented at the 2019 ASCO Annual Meeting, June 2, 2019; Chicago, IL.

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