Isatuximab improves progression-free survival in patients receiving carfilzomib–dexamethasone treatment for multiple myeloma

1. Higher rates of treatment response were observed in patients receiving isatuximab with carfilzomib–dexamethasone than carfilzomib–dexamethasone alone.

2. Improved median progression-free survival and estimated survival rates two years after randomization in favor of the isatuximab group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Multiple myeloma (MM) remains an incurable hematologic malignancy, typically treated with immunomodulators and targeted therapies. Isatuximab is an IgG1 anti-CD38 monoclonal antibody which has shown efficacy in treating multiple myeloma when given in combination with dexamethasone and several immunomodulatory agents. The IKEMA randomized, phase 3, open-label, multicenter clinical trial evaluated the benefit of adding isatuximab to carfilzomib–dexamethasone treatment regiments for refractory multiple myeloma. The primary efficacy outcome was progression-free survival from time of randomization; secondary endpoints included treatment response rate, overall survival, and minimal residual disease (MDR) levels as measured using next-generation sequencing. The results of this study demonstrated higher rates of progression-free survival when isatuximab was added to carfilzomib–dexamethasone treatment regimen. Additionally, the MDR negative rates were twice as high in the isatuximab group than in the carfilzomib–dexamethasone only group. Likewise, overall treatment response improved in the isatuximab group compared to the carfilzomib–dexamethasone only group. However, addition of isatuximab was associated with higher rates of serious treatment-emergent adverse events (TEAEs) compared to carfilzomib–dexamethasone only, resulting in treatment discontinuation for a subset of patients. In particular, the rates of upper respiratory infections, pneumonia, and bronchitis were more common in the isatuximab group.

Click to read the study in The Lancet

Relevant Reading: Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design

In-Depth [randomized controlled trial]: This study included 302 patients from 69 international centers. Participants were randomly assigned in a 3:2 ratio to the isatuximab plus carfilzomib–dexamethasone and carfilzomib–dexamethasone control groups, respectively. Participant demographics were comparable between groups. Multiple myeloma subtype, cytogenetic status, and staging at time of randomization were documented at the time of study entry. At the median follow-up time point of 20.7 months, the isatuximab group demonstrated statistically significant improvement in progression-free survival compared to control (HR 0.53, 99% CI [0.32–0.89], one-sided p=0.0007). The estimated rate of progression-free survival at 2 years was 68·9% (95% CI [60.7–75.8]) in the isatuximab group, compared to 45.7% [35.2–55.6] in the control group. The strength of treatment response was significant for the subcategories “very good partial response” or better. The MDR negativity rate was 30% in the isatuximab group versus 13% in the control group (p=0.0004). In terms of treatment-emergent adverse events (TEAEs), both groups had comparable overall rates of TEAEs. However, the isatuximab group demonstrated higher rates of serious TEAEs (grade 3 or worse), most commonly infusion-related infections, cardiac complications, and thromboembolic events. The results of this study are limited by the open-label nature of the trial, which may have biased outcomes. Additionally, Black or African American patients constituted only 3% of the trial cohort. Despite these limitations, the results of this trial support the addition of isatuximab to carfilzomib–dexamethasone treatment regiments, improving survival and treatment efficacy in patients with relapsed multiple myeloma.

Image: PD

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