Background
Phase 3, open-label, randomized controlled trial (IFM 2020-05). N=270 patients with newly diagnosed transplant-ineligible multiple myeloma, aged 65–79 years. All patients received isatuximab + lenalidomide + dexamethasone backbone; the experimental arm added bortezomib. Primary endpoint was MRD-based to address whether quadruplet vs triplet isatuximab regimens differed in depth of disease eradication.
Interventions and follow up
Arm A (Isa-VRd): Isatuximab 10 mg/kg IV (weekly cycle 1, then every 2 weeks) + bortezomib 1.3 mg/m² SC (days 1, 4, 8, 11 of 21-day cycles x 8 cycles then weekly) + lenalidomide 25 mg PO + dexamethasone 20 mg PO, induction then maintenance with Isa-Rd.
Arm B (Isa-Rd): Isatuximab 10 mg/kg IV (every 2 weeks) + lenalidomide 25 mg PO + dexamethasone 20 mg PO, continuous until progression or unacceptable toxicity.
Primary endpoint: MRD-negativity rate (10⁻⁵ by NGS) at 18 months from randomization
Median follow-up: ~24 months
Arm B (Isa-Rd): Isatuximab 10 mg/kg IV (every 2 weeks) + lenalidomide 25 mg PO + dexamethasone 20 mg PO, continuous until progression or unacceptable toxicity.
Primary endpoint: MRD-negativity rate (10⁻⁵ by NGS) at 18 months from randomization
Median follow-up: ~24 months
Results
MRD-negativity (10⁻⁵) at 18 mo: 53% vs 26%, P<.001
MRD-negativity (10⁻⁵) at 12 mo: 51% vs 21%
MRD-negativity (10⁻⁶) at 18 mo: 36% vs 17%
PFS: Directionally favoring Isa-VRd; data immature at primary analysis
MRD-negativity (10⁻⁵) at 12 mo: 51% vs 21%
MRD-negativity (10⁻⁶) at 18 mo: 36% vs 17%
PFS: Directionally favoring Isa-VRd; data immature at primary analysis
Adverse events
Neurologic (Isa-VRd vs Isa-Rd): Grade ≥3 peripheral neuropathy 6.0% vs 0.7%.
Hematologic: Grade ≥3 neutropenia 26.0% vs 23.0%.
Infection / discontinuation: Infections any grade 71.0% vs 68.0%; treatment discontinuation 8.1% vs 7.4%.
Hematologic: Grade ≥3 neutropenia 26.0% vs 23.0%.
Infection / discontinuation: Infections any grade 71.0% vs 68.0%; treatment discontinuation 8.1% vs 7.4%.
Conclusions
Addition of bortezomib to an isatuximab + Rd backbone doubled MRD-negativity rates at 18 months in transplant-ineligible NDMM, demonstrating that quadruplet Isa-VRd achieves substantially deeper disease control than the triplet Isa-Rd, at the cost of added bortezomib-related neurotoxicity.
Key Limitations
MRD-negativity at 18 months is a surrogate endpoint; PFS and OS data were immature at primary analysis. Both arms contained isatuximab, making it impossible to assess the contribution of isatuximab alone vs bortezomib addition; direct comparison with non-isatuximab VRd is not possible. Patients aged 65–79 may not represent older or frail patients common in practice. Bortezomib-related neuropathy (6% grade ≥3) is clinically relevant in elderly patients.
Clinical Context
BENEFIT complements the larger IMROZ trial (Facon T et al, NEJM 2024), which demonstrated PFS benefit of Isa-VRd vs VRd in NDMM-TI. FDA approved isatuximab + VRd for transplant-ineligible NDMM in 2024, primarily based on IMROZ; ESMO and ASCO guidelines now incorporate isatuximab-based quadruplets in this setting. BENEFIT specifically addresses whether adding bortezomib to an isatuximab-Rd backbone adds MRD eradication benefit — it does, at the cost of added neuropathy.