Novel Treatment Combination Demonstrates Sustained Benefit in Multiple Myeloma Patients
A new treatment regimen, combining isatuximab, lenalidomide, dexamethasone, and bortezomib (Isa-VRd), has shown significantly improved sustained minimal residual disease (sMRD) negativity in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM), according to research presented at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida, on December 6, 2025. These long-term findings from the phase 3 BENEFIT trial reinforce Isa-VRd as a promising new standard of care, particularly for older and high-risk patients.
Long-Term Data Bolsters Isa-VRd’s Efficacy
The data, gathered from a 12-to-24-month analysis of the BENEFIT clinical trial (NCT04751877), compared Isa-VRd to a regimen without bortezomib (Isa-Rd). Initial results from the BENEFIT study indicated a better response and MRD negativity with Isa-VRd at a median follow-up of 18 months. However, analysis of sustained MRD (sMRD) was not possible at that time. Now, with a median follow-up of 33.4 months, researchers have, for the first time, presented compelling sMRD results.
Why sMRD Matters in Multiple Myeloma
Minimal residual disease (MRD) negativity – the absence of detectable myeloma cells remaining after treatment – is increasingly recognized as a critical prognostic indicator in hematologic malignancies. A comprehensive meta-analysis of 44 studies demonstrated a strong correlation between MRD negativity and improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma patients, regardless of their disease stage.
However, experts emphasize that sustained MRD negativity is even more predictive of durable responses. Achieving and maintaining MRD negativity for 6 or 12 months, rather than a single assessment, provides significantly improved prognostic granularity. “It’s becoming increasingly clear that a single MRD assessment is not always sufficient to predict long-term outcomes,” stated a hematologist involved in the study.
Isa-VRd Significantly Improves sMRD Rates
At the 24-month mark, 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) compared to Isa-Rd. Similar observations were made at the 10-6 threshold. While 29% of patients (78 total) had discontinued treatment, primarily due to disease progression, the sMRD data remained compelling.
Unique Challenges in Patients with t(11;14) Translocation
Researchers also examined sMRD in a subgroup of patients with the t(11;14) translocation, a common genetic abnormality in multiple myeloma associated with higher levels of BCL2 and more frequent CD20 expression. This translocation often presents with more complex clinical features, including light chain disease and immunoglobulin M diseases.
Interestingly, MRD negativity rates were consistently lower in this subgroup, mirroring observations from the phase 3 MIDAS (NCT04934475) study. Due to the limited number of patients with this translocation in the BENEFIT trial, subgroup-specific analyses were not possible. Investigators noted that patients with t(11;14) translocations may require more prolonged or intensified treatment to achieve MRD negativity. “This patient may require more prolonged exposure or maybe a stronger treatment to achieve MRD negativity,” explained a study investigator. .
Safety Profile Remains Favorable
The Isa-VRd regimen demonstrated a positive safety profile, with no increase in treatment-emergent adverse events compared to Isa-Rd. Importantly, no new safety signals were observed, even in high-risk patient populations.
A New Standard of Care Emerges
These findings strongly support the use of Isa-VRd as a new standard of care for transplant-ineligible patients with newly diagnosed multiple myeloma, particularly those who are older or considered high-risk. “The data provide an important treatment option for frontline disease control and reinforce Isa-VRd as a new standard of care for TI NDMM,” concluded a lead researcher. “sMRD is a powerful longitudinal marker for disease control.”
