Long Term BENEFIT Data Affirm Isa-VRd as Standard of Care in Transplant-Ineligible NDMM

New research presented at the 67^th American Society of Hematology Annual Meeting and Exposition, taking place December 6 through 9 in Orlando, Florida, demonstrates improved sustained minimal residual disease (sMRD) negativity after treatment with isatuximab (Sarclisa; Sanofi) plus lenalidomide (Revlimid; Bristol Myers Squibb) and dexamethasone with bortezomib (Velcade; Takeda Pharmaceuticals) (Isa-VRd) in transplant ineligible (TI) patients with newly diagnosed multiple myeloma (NDMM).¹

What Did the BENEFIT Study Investigators Originally Find?

The results, presented during an oral abstract session, were gathered from a 12-to-24-month analysis of data from the multicenter, phase 3, randomized BENEFIT clinical trial (NCT04751877). Investigators in the trial compared the Isa-VRd regimen with Isa-Rd, the regimen without bortezomib.^1-3

In the original BENEFIT study, patients treated with Isa-VRd had a better response and MRD negativity at a median follow-up of 18 months compared with those treated with Isa-Rd. However, at the February 2025 cut-off point, the data were not yet mature enough for an analysis of sMRD. Now, after a median of 33.4 months (95% CI, 33.0–34.0), sMRD results can be presented for the first time.^1,3

Why is sMRD Negativity an Important Prognostic Marker in NDMM?

MRD negativity has been rigorously examined as a prognostic indicator of progression-free survival (PFS) and overall survival (OS) in patients with hematologic malignancies. One large meta-analysis of 44 studies of patients with multiple myeloma found that MRD negativity was associated with meaningfully improved outcomes regardless of disease setting.⁴

Although a single-point MRD negativity result can serve an important purpose when evaluating a patient’s disease progression and treatment response, sustaining such a status for a long period of time demonstrates an even stronger and more durable response. For patients with sustained MRD negativity over a period of 6 or 12 months compared with a one-time confirmation, PFS and prognostic granularity are significantly improved.^4,5

"It's becoming increasingly clear that a single MRD assessment is not always sufficient to predict long-term outcomes,” Arthur Bobin, MD, an investigator of the study and hematologist at Poitiers University Hospital in Poitiers, France, said during the session.¹

Was sMRD Improved With Isa-VRd Compared With Isa-Rd?

At the new, long-term follow-up point in the current analysis, 78 patients (29%) had discontinued treatment, mainly due to progressive disease. In the intention-to-treat population, the sMRD negativity rate at the 10^-5 threshold was significantly higher in the Isa-VRd arm (OR = 2.26; 95% CI, 1.50—4.80; P = .0007) at 24 months. Observations were similar for sMRD at the 10^-6 threshold, the investigators reported.¹

The authors specifically examined sMRD in a subgroup of patients with TI NDMM with the translocation of chromosomes 11 and 14 [t(11;14)]. This translocation is the most common primary event in MM and represents a unique subset of disease, featuring higher levels of BCL2 and more frequent expression of CD20. It is also associated with more complex clinical presentations, including light chain disease and immunoglobulin M diseases. sMRD in this population was once again evaluated at both 10^-5 and 10^-6 thresholds.^1,6

At all points up to 24 months, MRD negativity rates were consistently lower in this subgroup. They noted that this observation was similar to those discussed in the phase 3 MIDAS (NCT04934475) study. However, because of the small number of patients per group, the investigators could not perform subgroup-specific analyses. Bobin explained that patients with t(11;14) translocations can experience delays in improvements of MRD negativity and may respond more slowly to treatment, requiring optimal treatment tailoring and management.^1,7,8

"This patient may require more prolonged exposure or maybe a stronger treatment to achieve MRD negativity,” Bobin discussed.¹

Safety was positive in patients treated with Isa-VRd, with no increase in treatment-emergent adverse events compared with Isa-Rd. Importantly, no new safety signals were observed in either treatment arm, including in high-risk patients. Overall, this sMRD data supports the use of Isa-VRd as a new standard of care for patients with TI NDMM, especially those at an older age or those with high-risk disease.¹

“The data provide an important treatment option for frontline disease control and reinforce Isa-VRd as a new standard of care for TI NDMM,” Bobin concluded. “sMRD is a powerful longitudinal marker for disease control."¹

REFERENCES

1. Bobin A, Lambert J, Corre J, et al. Sustained minimal residual disease (sMRD) negativity in transplant ineligible newly diagnosed multiple myeloma treated with isatuximab plus lenalidomide and dexamethasone with bortezomib (Isa-VRd) versus isa-rd: 12-24-month data from the phase 3 benefit trial (IFM 2020-05). Presented: 67^th American Society of Hematology (ASH) Annual Meeting and Exposition; December 6, 2025; Orlando, Florida. Accessed on ASH Virtual Platform on December 6, 2025. https://meetings-api.hematology.org/api/abstract/vmpreview/298506

2. Multicenter open label phase 3 study of isatuximab plus lenalidomide and dexamethasone with/without bortezomib in the treatment of newly diagnosed non frail transplant ineligible multiple myeloma elderly patients. ClinicalTrials.gov Identifier: NCT04751877. Last Updated Septembeer 7, 2022. Accessed December 6, 2025. https://clinicaltrials.gov/study/NCT04751877

3. Leleu X, Hulin C, Lambert J, et al. Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nat Med. 2024;30(8):2235-2241. doi:10.1038/s41591-024-03050-2

4. Munshi NC, Avet-Loiseau H, Anderson KC, et al. A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma. Blood Adv. 2020;4(23):5988-5999. doi:10.1182/bloodadvances.2020002827

5. Bianchi G. Sustained minimal residual disease in myeloma. Blood. 2022;139(4):469-471. doi:10.1182/blood.2021013199

6. Bal S, Kumar SK, Fonseca R, et al. Multiple myeloma with t(11;14): unique biology and evolving landscape. Am J Cancer Res. 2022;12(7):2950-2965. PMID: 35968339.

7. Perrot A, Lambert J, Hulin C, et al. Measurable residual disease-guided therapy in newly diagnosed myeloma. N Engl J Med. 2025;393(5):425-437. doi:10.1056/NEJMoa2505133

8. Minimal residual disease adapted strategy (MIDAS). ClinicalTrials.gov Identifier: NCT0434475. Last Updated November 7, 2024. Accessed December 6, 2025. https://clinicaltrials.gov/study/NCT04934475