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Isatuximab + Carfilzomib and Dexamethasone in Early vs Late Relapsed Multiple Myeloma
The addition of isatuximab (Isa) to carfilzomib (K) and dexamethasone (d) (Isa-Kd) improves progression-free survival (PFS) and depth of response with a manageable safety profile in both early and late relapse patients with multiple myeloma (MM), according to the results of a subgroup analysis of the IKEMA study conducted by Thomas Martin, MD, and colleagues. The researchers presented their findings in “Isatuximab plus carfilzomib and dexamethasone in patients with early versus late relapsed multiple myeloma: IKEMA subgroup analysis,” at the 64th American Society of Hematology Annual Meeting and Exposition.
Relapse occurs frequently in patients with MM requiring successive lines of treatment, and patients who experience early relapse within 12 months of initial therapy have worse outcomes.
“The primary endpoint of the study was progression-free survival as evaluated by an independent review committee and key secondary endpoints included overall response rates and rates of complete response, as well as MRD-negativity,” Dr Martin said. “A number of studies have highlighted that patients with multiple myeloma with suboptimal response to induction therapy, or early relapse, have been shown to have poor outcomes. These functionally high-risk patients are an unmet need.”
Results from the phase 3 IKEMA study (NCT03275285) confirmed that Isa-Kd significantly improved PFS compared with Kd in patients with relapsed MM (median PFS 35.7 [Isa-Kd] vs 19.2 months [Kd]; hazard ratio [HR] 0.58; 95.4% CI, 0.42–0.79), with a clinically meaningful increase in minimal residual disease negativity (MRD-neg; 33.5% vs 15.4%) and complete response (CR; 44.1% vs 28.5%) rates in the intent-to-treat population, with a manageable safety profile.
Patients who previously received one to three lines of therapy (LOT) were randomized 3:2 to receive Isa-Kd (n = 179) or Kd (n = 123) until progressive disease or unacceptable toxicity.
Early relapse was defined as patients who relapsed <12 months from initiation of the most recent LOT for patients with ≥2 prior LOT, <18 months for patients with 1 prior LOT, and <12 months from autologous stem-cell transplantation. Patients in the late relapse group were those who relapsed ≥12 months from initiation of the most recent LOT for those with ≥2 prior LOT and ≥18 months for patients with 1 prior LOT.
Median follow-up data at 44 months are based on a prespecified final PFS analysis of IKEMA; CR, MRD-neg, and safety were secondary endpoints.
There was a total of 107 early relapse patients (61/179 [34.1%] Isa-Kd vs 46/123 [37.4%] Kd) and 176 late relapse patients (104 [58.1%] Isa-Kd vs 72 [58.5%] Kd).
Both early and late relapse patients in the Kd arm had a median of 2 prior LOT; late relapse Isa-Kd arm had a median of 1 prior LOT (55.8% had 1 prior LOT with Isa-Kd vs 48.6% with Kd). The median PFS was found to be longer for patients treated with Isa-Kd vs Kd in both early relapse (24.7 vs 17.2 months; HR 0.662 [95.4% CI, 0.404-1.087]) and late relapse (42.7 vs 21.9 months; HR, 0.542 [95.4% CI, 0.353–0.833]) patients. In early relapse patients, overall response rates (ORR) were 82.0% vs 82.6% with Isa-Kd vs Kd, respectively. In late relapse patients, ORR were 90.4% vs 86.1% with Isa-Kd vs Kd, respectively.
More patients achieved very good partial response or better (early relapse: 67.2% vs 52.2%; late relapse: 76.0% vs 58.3%), MRD-neg (early relapse: 24.6% vs 15.2%; late relapse: 37.5% vs 16.7%), and MRD-neg CR (early relapse: 18.0% vs 10.9%; late relapse: 30.8% vs 13.9%) with Isa-Kd vs Kd, respectively.
Although Grade ≥3 and serious treatment-emergent adverse events (TEAEs) were similar in both treatment arms in early relapse patients, these were found to be higher in the Isa-Kd arm in late relapse patients. Rates of TEAEs leading to definitive discontinuation or death were similar in both treatment arms and across both early and late relapse patients.
Limitations of the study included the small numbers of patients and some imbalances in baseline characteristics between treatment arms and between early and late relapse patients.
“In this post hoc subgroup analysis of IKEMA, the addition of Isa to Kd resulted in clinically meaningful improvement in PFS and depth of response with a manageable safety profile in both early and late relapse patients, consistent with the benefit observed in the overall IKEMA study population,” Dr Martin said.
“In early and late relapse patients who were refractory to the last regimen, PFS and depth of response was higher with Isa-Kd vs Kd,” he concluded. “Overall, these results support Isa-Kd as a standard-of-care regimen for patients with relapsed myeloma regardless of whether they have early or late relapse.”
Facon T, Moreau P, Baker R, et al. Isatuximab Plus Carfilzomib and Dexamethasone in Patients with Early Versus Late Relapsed Multiple Myeloma: IKEMA Subgroup Analysis. Presented at the 64th ASH Annual Meeting and Exposition. December 10-13, 2022. Abstract 753. Funded by Sanofi.
