Iberdomide Plus Daratumumab or Bortezomib Shows Promising Clinical Activity in Relapsed/Refractory Myeloma

Triplet combinations consisting of iberdomide with dexamethasone and daratumumab (IberDd) or bortezomib and dexamethasone (IberVd) demonstrated favorable tolerability profiles and promising clinical activity in patients with heavily pretreated multiple myeloma (MM), according to findings from a phase I/II trial presented at the 2020 American Society of Hematology annual meeting.

“The promising clinical activity and favorable toxicity profile of the iberdomide-based triplets supports further development of these regimens in myeloma,” said lead study author Niels van de Donk, MD, of the VU University Medical Center in Amsterdam. “In addition, the favorable safety profile of iberdomide makes it an attractive drug for maintenance.”

Iberdomide, a cereblon E3 ligase modulator, has exhibited potent direct anti-tumor activity and immune stimulatory effects in preclinical studies and with dexamethasone in previous reports. In this report, Dr. van de Donk discussed the safety and efficacy of the two triplet regimens in patients with relapsed/refractory MM – 27 patients were assigned to IberDd and 23 were assigned to IberVd.

The investigators noted that this was a heavily pretreated patient population, with almost one-half of patients in both groups having triple class-refractory disease. The median prior lines of therapy was 4 in the IberDd cohort and 6 in the IberVd cohort. Prior therapies included pomalidomide or lenalidomide, plus a proteasome inhibitor (PI). Patients had experienced disease progression within 60 days of their last MM treatment. All patients in the study were refractory to their last treatment.

In the IberDd group, participants received escalating doses of iberdomide on days 1 through 21, along with daratumumab 16 mg/kg on days 1, 8, 15, and 22 in cycles 1 to 2, days 1 and 15 in cycles 3 through 6, and day 1 in cycle 7 and beyond. In the IberVd group, patients received iberdomide on days 1 through 14 with bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of cycles 1 to 8 and on days 1 and 8 of cycle 9 and beyond. Dexamethasone was administered weekly in both groups.

The doses of iberdomide ranged from 1.0 to 1.6 mg, but, after a receiving a median of 4 treatment cycles in the IberDd group and 6 in the IberVd group, the maximum tolerated dose and recommended phase II dose had not yet been reached in either cohort. As of October 14, 2020 (data cutoff), 44% of patients in each group were still on treatment.

The most common grade 3/4 treatment-emergent adverse events (TEAEs) in the study were hematologic. These included:

  • neutropenia (67% with IberDd and 26% with IberVd)
  • thrombocytopenia (15% and 26%)
  • anemia (30% and 13%)

Neutropenia was managed in both treatment groups with granulocyte colony-stimulating factor. No deaths occurred on study and few patients discontinued due to adverse events, the authors noted.

In the IberDd cohort, the overall response rate (ORR) was 42% across all dosing groups, which included one stringent complete response (sCR), two complete responses (CRs), two very good partial responses (VGPRs), and 6 partial responses (PRs). Response rates in the IberVd-treated patients appeared to be slightly higher, with an ORR of 61% including one sCR, 5 CRs, and 8 PRs.

The median time to response was 4.1 weeks with IberDd and 3.6 weeks with IberVd. The median duration of response, however, was not reached in either cohort.

Based on these data, iberdomide 1.6 mg was selected as the recommended phase II dose when used in combination, and enrollment into these dosing cohorts in both triplet combinations is ongoing. Although the study’s findings are limited by the small sample size, Dr. van de Donk and colleagues concluded that these results support the further development of iberdomide-based regimens in MM, with phase III trials planned to evaluate these combinations.

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

Reference

van de Donk N, Popat R, Larsen J, et al. First results of iberdomide (IBER; CC-220) in combination with dexamethasone (DEX) and daratumumab (DARA) or bortezomib (BORT) in patients with relapsed/refractory multiple myeloma (RRMM). Abstract #724. Presented at the 2020 ASH Annual Meeting, December 7, 2020.