Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial

In transplant-ineligible (TI) patients with newly diagnosed multiple myeloma (NDMM), adding an anti-CD38 monoclonal antibody to lenalidomide and dexamethasone has become a leading standard of care, exemplified by daratumumab-Rd (DRd) in MAIA with a median PFS of 62 months and MRD negativity rates up to 31%. Isatuximab, another anti-CD38 IgG1 with distinct epitope and mechanisms, has improved outcomes when added to standard backbones, but had not been studied with Rd in NDMM TI. Bortezomib scheduling has evolved from twice-weekly to weekly administration in 28-day regimens to preserve efficacy with better tolerability in TI populations. Given the strong DRd results and emerging quadruplet strategies (e.g., IMROZ and CEPHEUS with twice-weekly bortezomib), the BENEFIT/IFM2020-05 trial tested whether adding weekly bortezomib to isatuximab-Rd (Isa-VRd) deepens response—especially MRD negativity—compared with IsaRd in NDMM TI patients aged 65–79 years.

Prior phase 3 data (MAIA) established DRd over Rd in NDMM TI, improving MRD negativity (e.g., 28.8% vs 9.2% at 10⁻⁵ in updated reports) and survival. Quadruplet regimens with daratumumab also improved MRD in TI settings (ALCYONE: D+VMP vs VMP achieved 26.9% vs 7.0% MRD negativity at 10⁻⁵ and 9.1% vs 0.8% at 10⁻⁶). In transplant-eligible (TE) NDMM, quadruplets such as DVRd (PERSEUS) yielded even higher MRD negativity (10⁻⁶: 65.1% vs 32.2% with VRd), highlighting the impact of ASCT and intensification. IMROZ (isatuximab + VRd vs VRd, twice-weekly bortezomib) also supports CD38-antibody quadruplets. These data frame the rationale to test Isa-VRd with a weekly bortezomib schedule versus IsaRd, aiming to exceed DRd-era MRD depth in TI patients while maintaining tolerability.

Design: BENEFIT/IFM2020-05 was an open-label, multicenter, randomized (1:1), phase 3 trial across 60 French centers (enrollment 7 Sep 2021–2 Sep 2022). Patients (NDMM, TI, age 65–79) were randomized to IsaRd or Isa-VRd until progression; 28-day cycles. Randomization stratification: age (<75/≥75), baseline cytogenetic risk (FISH-defined), and center type. Eligibility: Key inclusion included NDMM per IMWG criteria requiring therapy (SLiM-CRAB), measurable disease, ECOG 0–2, frailty score <2, adequate marrow and organ function, life expectancy >6 months. Key exclusions included other plasma cell dyscrasias (e.g., amyloidosis, smoldering myeloma), significant uncontrolled comorbidities (e.g., cardiac), active severe infections, recent major surgery, prior systemic MM therapy (except short emergent steroids), active HBV/HCV without control, and conflicting investigational treatments. Interventions: All patients received isatuximab + lenalidomide + dexamethasone, with bortezomib per arm assignment. Isatuximab 10 mg/kg IV: weekly (days 1,8,15,22) cycle 1; then q2wk (days 1,15) cycles ≥2; then q4wk (day 1) cycles ≥13 to progression. Lenalidomide 25 mg PO days 1–21 each cycle to progression. Dexamethasone 20 mg PO weekly (days 1,8,15,22) through cycle 12 then stopped. In the Isa-VRd arm, bortezomib 1.3 mg/m² SC weekly (days 1,8,15) cycles 1–12; then days 1,15 cycles 13–18; permanently stopped after cycle 18. After 18 months, both arms continued isatuximab + lenalidomide until progression. Endpoints: Primary endpoint was MRD negativity at 10⁻⁵ at 18 months from randomization. Key secondary endpoints included response rates (ORR, ≥VGPR, ≥CR), MRD at different timepoints/thresholds (10⁻⁴, 10⁻⁵, 10⁻⁶), PFS, OS, and safety. MRD was centrally assessed on bone marrow in patients with ≥PR at 18 months, primarily by NGS (typical sensitivity 10⁻⁴; 10⁻⁵ and 10⁻⁶ analyses reported) with MFC backup (10⁻⁴) if NGS failed. Patients not evaluated for MRD or with <PR were considered MRD-positive at 10⁻⁵. Statistics: The study planned 270 patients to provide 80% power to detect an absolute improvement in 18-month MRD negativity from 15% (IsaRd) to 30% (Isa-VRd) at two-sided alpha 0.05, allowing for dropouts (ITT primary analysis). MRD endpoints used mixed logistic regression adjusting for stratification factors; ORs and 95% CIs reported (Wald test). Time-to-event outcomes used Kaplan–Meier (or Gray’s method for competing risks) and Cox models (HRs with 95% CIs). No interim analyses; two-sided alpha 0.05; analyses conducted in R 4.2.1. Safety included all treated patients.

- Enrollment and treatment: 307 screened; 270 randomized (ITT), 135 per arm; all treated. At data cutoff (25 Mar 2024), discontinuation of at least one study drug occurred in 19% overall (30 IsaRd; 20 Isa-VRd), most commonly for progression (59% of discontinuations). - Primary endpoint (MRD 10⁻⁵ at 18 months): Isa-VRd 53% (71/135; 95% CI 44–61) vs IsaRd 26% (35/135; 95% CI 19–34); OR 3.16 (95% CI 1.89–5.28), P < 0.0001. Benefit consistent across prespecified subgroups and observed as early as 12 months at 10⁻⁴ and 10⁻⁵; improvements also seen at 10⁻⁶. - Response: ≥CR at 18 months higher with Isa-VRd (58%) vs IsaRd (31%); OR 2.97 (95% CI 2–5), P < 0.0001. Combined endpoint of ≥CR plus MRD negativity was 37% vs 17% (P = 0.0003). Time to first ≥PR and ≥VGPR was shorter with Isa-VRd: median time to ≥PR 0.95 vs 0.99 months (HR 1.30, 95% CI 1.01–1.67; P = 0.040); median time to ≥VGPR 2.1 vs 3.7 months (HR 1.65, 95% CI 1.27–2.14; P = 0.0002). - Survival (immature): Median follow-up 23.5 months; progression events: 21 (IsaRd) vs 13 (Isa-VRd); deaths: 10 vs 11. Estimated 24-month PFS: 80.0% (95% CI 73.3–87.4) IsaRd vs 85.2% (95% CI 79.2–91.7) Isa-VRd. Estimated 24-month OS: 91.5% (95% CI 86.5–96.8) vs 91.1% (95% CI 86.1–96.4). - Treatment intensity: Median relative dose intensity—bortezomib 91.6% (95% CI 82–96); isatuximab 95.8% IsaRd vs 96.1% Isa-VRd; lenalidomide 91.0% vs 91.7%; dexamethasone 97.9% vs 95.8%. - Safety: Common AEs (any grade) included neutropenia (61% IsaRd; 57% Isa-VRd), diarrhea (48% both), infections (36–47%). Thrombocytopenia higher with Isa-VRd (27% any grade; 12% ≥G3) vs IsaRd (14% any; 5% ≥G3). Neuropathy more frequent with Isa-VRd (any grade 52%; ≥G2 27%, including 4 with G3) vs IsaRd (28%; ≥G2 10%, including 1 with G3). Sixteen (10%) Isa-VRd patients discontinued bortezomib due to ≥G2 nervous system disorders; overall, 164 ≥G2 AEs led to temporary/permanent bortezomib discontinuation in 79 patients. Second primary malignancies occurred in 12 patients (6 per arm), largely solid tumors; one MDS case in Isa-VRd. Causes of death were comparable across arms.

Adding weekly bortezomib to isatuximab, lenalidomide, and dexamethasone significantly deepened responses, doubling the 18-month MRD 10⁻⁵ negativity rate and increasing ≥CR and CR+MRD negativity composite endpoints versus IsaRd in NDMM TI patients aged 65–79 years. These gains were consistent across clinically relevant subgroups, including higher-risk disease, and were evident as early as 12 months at multiple MRD thresholds (10⁻⁴ to 10⁻⁶). While PFS and OS data are still immature and not yet significantly different, the magnitude of MRD improvement—a validated surrogate for survival in NDMM, including TI populations—supports the expectation of downstream survival benefit. Safety profiles were consistent with known class effects; neuropathy and thrombocytopenia were higher with the quadruplet, reflecting bortezomib exposure, but overall relative dose intensity remained high and treatment discontinuations due to AEs were manageable. Collectively with IMROZ, these findings support Isa-VRd as a new standard of care in NDMM TI. Optimization of bortezomib scheduling (weekly vs twice-weekly density and duration) and long-term tolerability remains an area for further study.

The phase 3 BENEFIT trial demonstrates that Isa-VRd significantly improves MRD negativity and depth of response over IsaRd in transplant-ineligible NDMM, with consistent benefits across subgroups and acceptable tolerability. Together with complementary data from IMROZ, Isa-VRd should be considered a new standard of care for NDMM TI patients aged 65–79 years. Future work should refine proteasome inhibitor scheduling to mitigate neuropathy while preserving efficacy, assess regimens tailored to frail patients (including steroid-sparing approaches), evaluate subcutaneous isatuximab formulations, and explore fixed-duration maintenance strategies to balance long-term safety, secondary malignancy risk, and quality of life without compromising efficacy.

- Survival outcomes are immature at a median follow-up of 23.5 months, limiting conclusions on PFS/OS. - Upper age limit of 79 years restricts generalizability to older or frail TI patients. - Intravenous isatuximab and prolonged bortezomib (up to 18 months) may impact convenience and neuropathy risk. - Continuous isatuximab + lenalidomide until progression; fixed-duration strategies were not tested. - Open-label design (although MRD assessment was centralized and blinded) and single-country enrollment (France) may affect external validity. - Increased neuropathy and thrombocytopenia with Isa-VRd reflect bortezomib exposure and warrant careful management.