The three-drug combination of the CD38-targeting antibody isatuximab plus carfilzomib and dexamethasone significantly improved progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma, compared with carfilzomib and dexamethasone alone, according to interim analysis data from the IKEMA trial.
“[These results suggest] isatuximab plus carfilzomib and dexamethasone represents a potential new standard of care for patients with relapsed multiple myeloma,” said Philippe Moreau, MD, of University Hospital Hôtel-Dieu in Nantes, France, who presented the results as a late-breaking abstract at EHA25 Virtual, the 25th European Hematology Association Annual Congress.
The phase III randomized trial included 302 patients with relapsed or refractory disease who had received 1 to 3 prior lines of therapy, excluding carfilzomib. About 25% of patients had high-risk cytogenetics.
Participants received carfilzomib and dexamethasone alone (n=123) or with isatuximab (n=179).
The carfilzomib and dexamethasone treatment consisted of:
- Carfilzomib by infusion 20 mg/m2 days 1 and 2, and up to 56 mg/m2 thereafter on days 8 and 9 and 15 and 16 of each 28-day cycle
- dexamethasone 20 mg once weekly
In the three-drug arm, isatuximab 10 mg/kg was administered weekly for 4 weeks, then every 2 weeks.
Over a median follow-up of 20.7 months, treatment with the triplet regimen was associated with a 47% reduction in the risk of progression or death, compared with the two-drug regimen (hazard ratio [HR] = 0.531; 99% CI 0.318-0.889; p=0.007). The authors reported that the median PFS was not reached for the isatuximab group but was 19.15 months for the carfilzomib/dexamethasone group, which was similar to the estimated PFS with the two-drug regimen based on data from previous trials.
“[Carfilzomib and dexamethasone provide] a good control arm in this study,” Dr. Moreau commented, “and adding isatuximab on top of [carfilzomib and dexamethasone] improved the outcome of patients, with very good PFS results.”
He added that improvement in PFS was observed across all subgroups, including those with difficult-to-treat disease, such as older patients, those with high-risk cytogenetics, and those with renal impairment.
The overall response rate was 86.6% for the isatuximab combination, compared with 82.9% for the standard group. The difference in the proportion of patients achieving a very good partial response or better was more pronounced: 72.6% compared with 56.1% (p=0.0011).
Patients assigned to isatuximab also had clinically meaningful improvement in the depth of response, according to Dr. Moreau. Overall, 29.6% of patients assigned to receive isatuximab achieved measurable residual disease negativity compared with 13% of patients assigned to carfilzomib and dexamethasone alone.
“This is a striking improvement that can explain the PFS benefit for all patients,” Dr. Moreau said.
Time to next treatment also was significantly delayed with addition of isatuximab to carfilzomib and dexamethasone (HR=0.566; 95% CI 0.380-0.841).
At the time of interim data presentation, there was no difference in overall survival between the two arms.
Dr. Moreau noted that more patients in the isatuximab arm are still receiving treatment as of data presentation, with more patients in the standard arm discontinuing treatment due to progressive disease or an adverse event (AE; 53.7% vs. 37.4%). Most patients in both arms experienced a grade ≥3 AE (76.2% of the isatuximab-treated patients and 67.2% of the standard group), the most common of which were hypertension, anemia, thrombocytopenia, neutropenia, and pneumonia.
However, the investigators reported that, despite more grade ≥3 AEs, the addition of isatuximab did not increase mortality, serious treatment-emergent AEs, or events leading to discontinuation.
Study authors report relationships with Sanofi, which sponsored the trial.
Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (Ikema): interim analysis of a phase 3, randomized, open-label study. Abstract LB2603. Presented as part of EHA25 Virtual, June 14, 2020.