The risk of progression or death for patients with relapsed or refractory multiple myeloma was nearly halved with the addition of isatuximab to carfilzomib and dexamethasone, according to an interim analysis of the phase 3 IKEMA trial ().
After a median follow-up of 20.7 months, the median progression-free survival had not been reached for 179 patients treated with isatuximab (Sarclisa), carfilzomib (Kyprolis), and dexamethasone (together, known as Isa-Kd), compared with 19.5 months for 123 patients treated with carfilzomib and dexamethasone alone (Kd). The hazard ratio for progression free survival with the triple combination was 0.531 (P = .0007), reported coprincipal investigator Phillipe Moreau, MD, from the University Hospital Hôtel-Dieu in Nantes, France.
“The benefit of the triplet combination was observed across subgroups, including patients difficult to treat, such as [those with] high-risk cytogenetics or elderly patients,” he said in a late-breaking abstract presentation during the virtual annual congress of the European Hematology Association.
Isatuximab is an immunoglobulin G1 monoclonal antibody targeting a CD38 transmembrane glycoprotein on multiple myeloma cells, with a mechanism of action similar to that of another anti-CD38 antibody, daratumumab (Darzalex). Isatuximab is approved in the United States and Europe in combination with pomalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma after at least two prior lines of therapy.
A ‘me too’ agent?
It’s unclear, however, whether isatuximab offers any additional benefit over daratumumab, an agent approved for use both in front line therapy combinations and for patients with relapsed/refractory disease, said Brea C. Lipe, MD, a multiple myeloma specialist at the University of Rochester (N.Y.) Wilmot Cancer Institute, who was not involved in the study.
“Every time we get a new drug it’s nice to have another option, but it doesn’t really add anything different from daratumumab at this point,” she said in an interview.
Dr. Lipe noted the IKEMA results are similar to those seen in the, comparing carfilzomib, dexamethasone, and daratumumab to carfilzomib/dexamethasone alone in patients with relapsed/refractory myeloma. In addition, it’s unknown whether patients with disease that is refractory to daratumumab could benefit from isatuximab, she said.
Although isatuximab has been touted as offering more rapid and more convenient dosing than daratumumab, the introduction of rapid infusion and subcutaneous administration of daratumumab has negated any theoretical advantage of the newcomer, Dr. Lipe added.
In the IKEMA trial, 302 patients with relapsed/refractory multiple myeloma who’d received one to three prior lines of therapy were stratified by the number of prior lines and by revised Multiple Myeloma International Staging System (R-ISS) and were then randomized on a 3:2 basis to treatment with carfilzomib 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of cycle 1 and 56 mg/m2 on the corresponding days of each subsequent cycle plus dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle, with or without isatuximab. The antibody was dosed 10 mg/kg on days 1, 8, 15, and 22 in cycle 1 then every 2 weeks thereafter.
Treatments were continued until disease progression, unacceptable toxicity, or patient choice intervened.
At a prespecified interim analysis, the trial met its primary endpoint of a minimum 41% risk reduction in the hazard rate for progression free survival (PFS), with an actual risk reduction of 47%.
An analysis of PFS by subgroup showed significant benefits with the triple combination for patients aged 65 years and older, those with baseline estimated glomerular filtration rates below 60 mL/min per 1.73 m2, those with more than one prior line of therapy, those who had not previously received a proteasome inhibitor (e.g., bortezomib) or immunomodulatory agent (e.g., lenalidomide), those with high-risk cytogenetic status, and those with R-ISS stage II at study entry.
Overall response rates were similar between the study arms, at 86.6% with Isa-Kd and 82.9% with Kd, but the rate of very good partial responses or better was significantly higher with the triplet, at 72.6% versus 56.1% (P = .0011). The rate of minimal residual disease negativity was also significantly lower with Isa-Kd in the intent-to-treat population, at 29.6% versus 13%, respectively (P = .0004).
Overall survival data were not mature at the time of data cutoff and will be reported later, Dr. Moreau said.
Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 76.8% of patients on the triplet and 67.2% of those on Kd. The incidences of death, serious TEAEs, or adverse events leading to discontinuation of therapy did not differ markedly between the treatment arms, however. Grade 3 or greater cardiac failure occurred in seven patients treated with the triplet (4%) and five treated with Kd (4.1%); respective rates of grade 3 or greater hematologic abnormalities included anemia in 22% and 19.7%, neutropenia in 19.2% and 7.4%, and thrombocytopenia in 29.9% and 23.8%.
The primary completion date for the trial is estimated to occur in November 2020, with final results in November 2023.
The study was sponsored by Sanofi. Dr. Moreau disclosed honoraria and a consulting or advisory role with several companies, not including Sanofi. Dr. Lipe disclosed impending advisory board activity for Janssen.
SOURCE: Moreau P et al. EHA Congress, .