Isa-VRd Sustains and Deepens MRD Negativity in Transplant-Ineligible Myeloma

A new landmark analysis of the phase 3 IMROZ trial (NCT03319667) shows that isatuximab (Sarclisa) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Isa-VRd) followed by isatuximab plus lenalidomide and dexamethasone (Isa-Rd) maintenance not only achieves higher rates of minimal residual disease (MRD) negativity than bortezomib, lenalidomide, and dexamethasone (VRd) followed by lenalidomide and dexamethasone (Rd) alone, but sustains and deepens those rates throughout up to 60 months of observation, including after bortezomib is withdrawn during the maintenance phase, according to results published in Blood.¹

The publication highlights the dynamics of MRD conversion and sustained negativity over time, representing what the authors describe as the first detailed MRD dynamics analysis in transplant-ineligible patients with newly diagnosed multiple myeloma.

MRD Rates by Study Time Point

The findings expand upon the primary IMROZ analysis which established Isa-VRd’s progression-free survival (PFS) benefit and superior MRD negativity rates at an earlier timepoint.

In the intent-to-treat (ITT) population, MRD negativity rates at the 10^-⁵ sensitivity threshold diverged progressively between arms throughout both the induction and maintenance phases. At 12 months of maintenance, 54.0% of patients in the Isa-VRd/Isa-Rd arm were MRD negative vs 39.2% in the VRd/Rd arm (OR, 1.81; 95% CI, 1.11-2.98). By 60 months, this separation widened substantially with 76.1% vs 40.0% (OR, 4.59; 95% CI, 1.34-17.04). Notably, patients in the quadruplet arm continued to convert from MRD positive to MRD negative through later maintenance time points even after bortezomib discontinuation, whereas the VRd/Rd arm’s cumulative MRD negativity curve plateaued after month 48, with no new MRD-negative results beyond that point.

Achieving MRD negativity despite bortezomib withdrawal raised the hypothesis that the regimen may promote remodeling of the tumor microenvironment during the induction phase that persists during lenalidomide-based maintenance, though additional studies are needed to test this hypothesis, the investigators wrote.

Fewer Relapses to MRD Positivity, Longer TTP When Relapse Occurs

Among patients who were MRD negative at the end of induction, far fewer in the Isa-VRd/Isa-Rd arm subsequently converted to MRD positivity during maintenance (5.6% vs 26.9% at 24 months, and 12.3% vs 34.8% at 36 months). In a landmark analysis, patients who did convert from MRD negativity at induction to MRD positivity during maintenance still derived a significant time-to-progression (TTP) benefit with Isa-VRd/Isa-Rd vs VRd/Rd (HR, 0.236; 95% CI, 0.089-0.624; P =.0036). A separate landmark analysis examining conversion from MRD negativity to positivity at any time point confirmed this TTP benefit (HR, 0.275; 95% CI, 0.114-0.664; P =.0041). These findings suggest that even when MRD control is ultimately lost, the quadruplet regimen provides a meaningful delay in subsequent disease progression.

Conversely, among patients who were MRD positive at the end of induction, a higher proportion in the Isa-VRd/Isa-Rd arm converted to MRD negativity during maintenance (36.1% vs 18.0% at 24 months and 48.2% vs 33.3% at 36 months) with conversion rates increasing over time with the quadruplet. This pattern suggests that continued isatuximab-based maintenance may rescue responses in patients who did not achieve MRD negativity during induction.

Sustained MRD Negativity: Two- to Threefold Advantage

Rates of sustained MRD negativity were approximately two- to threefold higher with Isa-VRd/Isa-Rd than with VRd/Rd across all durations evaluated. At the 10⁻⁵ threshold, sustained MRD negativity for 12 or more months was achieved by 46.8% vs 24.3% of ITT patients (OR, 2.73; 95% CI, 1.80-4.14), and for 24 or more months by 35.8% vs 13.3% (OR, 3.65; 95% CI, 2.22-6.03). Sustained MRD negativity for 36 or more months will be reported at later follow-up as the data were immature. Among patients achieving sustained MRD negativity for 24 or more months, PFS was similar between the arms, but more patients reached this benchmark with the quadruplet.

MRD-Negative Complete Response and Subgroup Consistency

In the ITT population, MRD-negative complete response (CR) rates at 60 months were 73.9% for Isa-VRd/Isa-Rd vs 40.0% for VRd/Rd, with a consistent advantage at each measured time point from induction through maintenance. Patients achieving MRD-negative CR in the quadruplet arm had significantly improved PFS compared with the VRd/Rd arm (HR, 0.539; 95% CI, 0.304-0.953; P =.0336) at the 10^-⁵ sensitivity threshold.

Benefits were consistent across all key patient subgroups defined by age, renal function, Revised International Staging System stage, cytogenetics (including high-risk), 1q21+ status, plasmacytoma presence, and frailty. The frailty subgroup finding is of particular clinical relevance: frail patients, often excluded from or underrepresented in clinical trials, demonstrated MRD negativity rates consistently favoring the quadruplet at each maintenance time point evaluated. The Blood paper notes this analysis employed frailty definitions per simplified International Myeloma Working Group scores of 2 or greater.

Clinical Implications

The investigators stated that the deepening of responses after a long treatment period warrants further investigation into the characteristics of these patients and the role of discontinuing bortezomib on MRD dynamics. They concluded that serial MRD assessment at end of induction and at multiple points during maintenance may provide actionable information to guide treatment decisions including selection, continuation, or discontinuation, and pointed to ongoing studies such as a phase 2 trial (NCT04113018) using an MRD-adapted strategy that could provide support for intensifying or reducing treatment based on MRD at key time points.²

REFERENCES

1. Orlowski RZ, Dimopoulos MA, Leleu X, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma: dynamics of MRD negativity in the IMROZ study. Blood. 2026;147(23):2760-2769. doi:10.1182/blood.2025030120

2. Bhutani M, Robinson M, Foureau D, et al. MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma. Blood Adv. 2025;9(3):507-519. doi:10.1182/bloodadvances.2024014417