Background
Phase 3, open-label, randomized controlled trial (IKEMA). N=302 patients with relapsed or refractory multiple myeloma after 1–3 prior lines of therapy. Randomized 3:2 (Isa-Kd vs Kd). Key eligibility: ECOG PS ≤2, measurable disease, no prior carfilzomib or anti-CD38 monoclonal antibody. Stratified by ISS stage, number of prior lines, and refractory status.
Interventions and follow up
Arm A (Isa-Kd): Isatuximab 10 mg/kg IV (weekly cycle 1, then every 2 weeks) + carfilzomib 20/56 mg/m² IV (days 1, 2, 8, 9, 15, 16 of 28-day cycles) + dexamethasone 20 mg PO/IV, until progression.
Arm B (Kd): Carfilzomib 20/56 mg/m² IV + dexamethasone 20 mg PO/IV, until progression.
Primary endpoint: Progression-free survival (by BICR)
Median follow-up: 20.7 months
Arm B (Kd): Carfilzomib 20/56 mg/m² IV + dexamethasone 20 mg PO/IV, until progression.
Primary endpoint: Progression-free survival (by BICR)
Median follow-up: 20.7 months
Results
mPFS: Not reached (Isa-Kd) vs 19.2 months (Kd), HR 0.53 (95% CI 0.32–0.89), P=.0011
12-mo PFS rate: 73% vs 56%
ORR: 87.0% vs 83.3%
≥VGPR rate: 72.6% vs 56.1%
MRD-negativity (10⁻⁵): 29.6% vs 13.0%
12-mo PFS rate: 73% vs 56%
ORR: 87.0% vs 83.3%
≥VGPR rate: 72.6% vs 56.1%
MRD-negativity (10⁻⁵): 29.6% vs 13.0%
Adverse events
Hematologic (Isa-Kd vs Kd): Grade ≥3 thrombocytopenia 29.9% vs 23.5%.
Cardiovascular: Grade ≥3 hypertension 19.4% vs 18.4%; cardiac failure any grade 4.2% vs 4.9%.
Administration / discontinuation: Infusion reactions any grade 45.8% (Isa-Kd, mostly grade 1–2); discontinuation for AEs 9.0% vs 11.1%.
Cardiovascular: Grade ≥3 hypertension 19.4% vs 18.4%; cardiac failure any grade 4.2% vs 4.9%.
Administration / discontinuation: Infusion reactions any grade 45.8% (Isa-Kd, mostly grade 1–2); discontinuation for AEs 9.0% vs 11.1%.
Conclusions
Isatuximab added to Kd (Isa-Kd) significantly improved PFS (HR 0.53) and response depth including MRD-negativity in 1–3 line RRMM without prior anti-CD38 or carfilzomib, establishing a new active combination in this setting.
Key Limitations
The trial was open-label (not blinded), introducing potential bias. The 3:2 randomization ratio (non-standard) was used for statistical efficiency but differs from typical 1:1 designs. Patients had to be anti-CD38 naïve, limiting applicability in the current era where many patients receive anti-CD38 frontline. The relatively short median follow-up meant the median PFS in the Isa-Kd arm was not reached at primary analysis — full benefit magnitude required maturation.
Clinical Context
Isa-Kd was FDA-approved in 2021 for RRMM after 1–3 prior lines and is recommended in ASCO and ESMO relapse guidance. It is particularly useful in anti-CD38-naïve patients who have received prior lenalidomide, offering an IMiD-free combination. Updated data continue to show sustained PFS benefit (HR 0.58 at ~44-month follow-up). IKEMA positions Isa-Kd as an effective alternative to daratumumab-based combinations in carfilzomib-naïve relapsed myeloma.