In patients with newly diagnosed multiple myeloma (MM) who are not eligible for stem cell transplant, the regimen of isatuximab plus lenalidomide, dexamethasone, and bortezomib (also known as Isa-VRd) shows sustained minimal residual disease (MRD) negativity in longitudinal assessments compared with the regimen without bortezomib (Isa-Rd).

“We found [in this updated analysis of the BENEFIT trial] that the improved efficacy of Isa-VRd, combined with its consistent safety profile, provides an important treatment option for frontline disease control, establishing [Isa-VRd] as a new standard of care for newly diagnosed, transplant-ineligible [multiple myeloma],” said Arthur Bobin, MD, Department of Hematology, Poitiers University Hospital, Poitiers, France, at American Society of Hematology (ASH) 2025 Annual Meeting.

“With a median follow-up of 33.4 months, we can now report for the first time sustained [minimal residual disease] results from the BENEFIT trial,” including high-risk multiple myeloma, said first author Bobin, while presenting the findings at the meeting.

Data from the recent phase 3 BENEFIT, along with the IMROZ trial, established that the combination of the anti-CD38 monoclonal antibody isatuximab with the standard first-line regimen of VRd as representing the best treatment regimen for patients with MM who are ineligible for transplantation due to factors including older age or comorbidities.

While the published BENEFIT trial showed significant improvements with Isa-VRd vs Isa-Rd in MRD negativity through month 12 (26% vs 53%; P < .0001), and greater complete responses (58% vs 33%; P < .0001), data on progression-free survival outcomes was still immature.

“As our field evolves, it has become increasingly clear that a single MRD assessment is not always sufficient to predict long term outcomes,” Bobin explained in the presentation.

“Longitudinal MRD evaluation — especially sustained MRD negativity for at least 12 months — appears to correlate even better with survival,” he said.

With longer-term data on a median of 33.4 months from the BENEFIT trial now available, Bobin and colleagues conducted the updated analysis, analyzing rates of sustained MRD between 12 months and 24 months.

In the original study, 270 patients with transplant ineligible MM were randomized 1:1 to either Isa-VRd or Isa-Rd, with bortezomib administered weekly for up to 18 months, dexamethasone permanently discontinued after 12 months, and isatuximab-lenalidomide continued until progression.

As of the current follow-up, 78 patients (29%) had discontinued treatment, including 31 (27%) in the Isa-VRd group and 47 (37%) in the Isa-Rd group, primarily due to progressive disease in both groups.

The median age at the follow-up analysis was 73 years, and about a third of patients were younger than 75 years. Their baseline characteristics were well-balanced in both study groups.

At as early as 6 months, 81% of patients in the Isa-VRd group had a very good partial response, and three patients had a complete response compared with a very good partial response of 64% and no patients having a complete response in the Isa-Rd group.

The complete response rates continued to be greater with the Isa-VRd group at 12- month, 18-month, and 24-month timepoints, reaching 72% in the Isa-VRd group at 24 months.

“Isa-VRd resulted in deep response rates, including complete response or greater, at all timepoints,” Bobin said.

Furthermore, at all three timepoints, the MRD negativity rate at 10^-5 remained significantly higher in the Isa-VRd group than in the Isa-Rd group (odds ratio [OR], 3.88 [P < .0001] at 12 months; OR, 3.16 [P < .0001] at 18 months; and OR, 2.26 [P = .002] at 24 months).

Similar MRD patterns were observed at the deeper 10^-6 threshold.

Overall, the sustained MRD negativity at 10^-5, defined as the proportion of patients with MRD negative results at the 10^-5threshold over 12 months without any MRD-positive results in-between, was more frequent in the Isa-VRd group vs the Isa-Rd group (34% vs 16%; OR, 2.73; P = .0007) as it was in the 10^-6 group (21% vs 7%; OR, 3.19; P = .003).

“This data confirms that the depth of response achieved with Isa-VRd is not only higher but also more durable vs Isa-Rd,” Bobin said.

Subgroup Analysis Finds No Differences in MRD Negativity Rates Between Groups

A further subanalysis evaluated carriers of the t(11;14) translocation, which is the most common genetic alteration in MM and was present in 31% of patients in the Isa-VRd group and 22% in the Isa-Rd group.

Among those patients, MRD negativity rates at 10^-5 and 10^-6 were consistently lower than those without the alteration at all timepoints up to 24 months, irrespective of the treatment group and despite a nonrisk profile, Bobin explained.

“The t(11;14)-positive subgroup appears to have lower MRD-negative rates at all timepoints, possibly due to delayed MRD-negative conversions,” he said. “The data suggests that these patients may require more prolonged exposure or maybe more intensive treatment to achieve MRD negativity.”

No new safety signals were observed in either treatment group, including in high-risk patients with MM, and there were no differences in adverse events between the two groups.

“These findings reinforce Isa-VRd as a new standard of care for transplant ineligible patients aged 65 to 79, and they also highlight that sustained MRD is a powerful longitudinal marker for disease control,” Bobin said.

Bortezomib Dosing Differences

The dosing of bortezomib in the BENEFIT trial was once-weekly for 18 months compared with the twice-weekly over 6-months regimen used in the previous IMROZ and CEPHEUS clinical trials.

Despite those dosing differences, “sustained MRD rates at 24 months were similar across studies, suggesting that total exposure — the number of injections — may matter more than short-term intensity,” Bobin noted.

The updated analysis does not yet show a significant difference in progression-free survival rates between the groups.

Bobin agreed with a comment from the audience that the sustained MRD negativity observed in the study suggests a likely eventual improvement in progression-free survival.

This study was funded by Sanofi. Bobin’s disclosures included relationships with Sanofi and Janssen-Cilag.