Isatuximab-Based Therapy Shows “Impressive” PFS Projections in NDMM

Although not yet statistically significant, the difference in progression-free survival (PFS) outcomes continues to grow with isatuximab-irfc (Sarclisa) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Isa-VRd) vs IsaRd alone among patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), and both regimens showed “impressive” projections for long-term PFS, according to a presentation on data from the phase 3 BENEFIT trial (NCT04751877) at the 23rd Annual International Myeloma Society (IMS) Meeting & Exposition.

What were the PFS and OS outcomes from the BENEFIT trial?

The estimated 48-month PFS rates were 65.7% (95% CI, 57.9%-74.5%) with IsaRd and 74% (95% CI, 66.9%-82%) with Isa-Vrd. The PFS restricted mean survival time was 38.6 months (95% CI, 36.1-41.2) and 40.5 months (95% CI, 38.1-42.9) in each respective arm for a difference of 1.9 months (95% CI, –1.6 to 5.4; P = .29). At 48 months, the OS rates were 85.8% (95% CI, 79.7%-92.4%) and 84.2% (95% CI, 78.1%-90.9%) with IsaRd and Isa-VRd, respectively. The mean restricted OS time was 44.5 months (95% CI, 42.7-46.3) and 43.9 months (95% CI, 42.1-45.8), reflecting a difference of –0.6 months (95% CI, –3.2 to 2.1; P = .68).

Of note, when accounting for a subgroup of patients with high-risk multiple myeloma, the estimated 48-month PFS rates were 40.2% (95% CI, 25.6%-63.1%) with IsaRd and 63.1% (95% CI, 49.8%-79.9%) with Isa-VRd. The restricted mean PFS values in the high-risk population were 32.3 months (95% CI, 26.2-38.4) with the triplet and 36.4 months (95% CI, 31.2-41.5) with the quadruplet.

In an extrapolation of PFS outcomes, the projected 120-month rates were 34% (95% CI, 23.5%-44.4%) with IsaRd and 47.6% (95% CI, 34.9%-59%) with Isa-VRd. Additionally, the extrapolated 120-month OS rates were 66.7% (95% CI, 52.6%-76.9%) and 66.1% (95% CI, 51.9%-75.9%) with each regimen.

“The difference [in survival time] grows over time across arms, but it’s not yet statistically significant. The long-term projection of PFS shows an impressive projection, particularly for the quadruplet regimen. Median PFS is expected…to be beyond 10 years. Even in the control arm, the projection at 10 years is very impressive with one-third clearly being free of disease relapse or death,” lead study investigator Xavier Leleu MD, PhD, professor, head of the Myeloma Clinic, and head of the Department of Hematology at Hôpital La Mileterie, stated in his presentation of the data. “We believe that there are no objections against the fact that minimal residual disease [MRD] difference initially based on bortezomib addition translate into survival, but it will take time because the control arm performed extremely well. Of course, we need more follow-up, and [we will] show more data in the years to come.”

How was the BENEFIT trial designed?

Investigators of the BENEFIT trial randomly assigned 270 patients with transplant-ineligible NDMM to receive Isa-VRd (n = 135) or IsaRd alone (n = 135) until progression or unacceptable toxicity. The treatment phase occurred up until cycle 18; an MRD assessment at 10^–5 took place afterwards. From cycle 19 until progression, all patients received isatuximab at 10 mg/kg plus lenalidomide at 25 mg.

The trial’s primary end point was MRD. Secondary end points included the complete response rate, the very good partial response or better rate, PFS, and OS. Patients 65 to 79 years old were eligible for enrollment. Investigators also classified patients as having high-risk multiple myeloma based on international genomic consensus staging.

In a previous analysis of the BENEFIT trial, after a median follow-up of 23.5 months, the MRD negativity rates at the 18-month assessment were 53% with Isa-VRd and 26% with IsaRd (OR, 3.16; 95% CI, 1.89-5.28; P <.0001). Additionally, the 24-month PFS rates were 85.2% and 80% in each respective arm; the median PFS was not reached in either arm. Grade 3 or higher treatment-emergent adverse effects (TEAEs) were reported in 69% and 67% of patients; additional safety data revealed serious TEAEs in 34% vs 35% of patients and any-grade peripheral neuropathy in 52% vs 28%.

In the latest analysis of the BENEFIT trial, investigators assessed the restricted mean survival time across both arms, defined as the average duration a patient lives without disease progression or death restricted to a pre-specified time point of 4 years. Additionally, 10-year OS and PFS outcomes were extrapolated from observed curves using 6 different parametric models fitted independently in each arm, which were classically recommended by National Institute for Health and Care Excellence Health Technology Assessment guidance.

With a median follow-up of 48.9 months, 109 and 102 patients in the Isa-VRd and IsaRd arms, respectively, were receiving ongoing therapy. In the Isa-VRd arm, 26 patients had progressive disease, and 21 died; these numbers were 39 and 20, respectively, in the IsaRd arm.

“The data confirm that Isa-VRd is a new [standard of care] for all [transplant-ineligible] NDMM subgroups, including [high-risk multiple myeloma],” Leleu wrote with coauthors in the presentation.

Reference

Leleu X, Lambert J, Bigot N, et al. 48-month survival analysis of the BENEFIT trial, isatuximab plus bortezomib, lenalidomide, and dexamethasone for transplant-ineligible newly diagnosed multiple myeloma patients. Presented at: 23rd International Myeloma Society Annual Meeting; September 23-26, 2026; Glasgow, Scotland. Abstract LBA-03.