Loading ...

TOPLINE:

Isatuximab combined with bortezomib, lenalidomide, and dexamethasone (Isa-VRd), followed by isatuximab-lenalidomide-dexamethasone (Isa-Rd) maintenance leads to higher rates of minimal residual disease (MRD) negativity and negative complete response in transplant-ineligible patients with newly diagnosed multiple myeloma compared with standard VRd/Rd therapy. At 60 months, more than 75% of patients receiving Isa-VRd/Isa-Rd achieved MRD negativity compared with 40% with VRd/Rd, with sustained MRD negativity rates more than doubled in the isatuximab arm.

METHODOLOGY:

• MRD status affects outcomes in both transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma, with MRD-negative patients demonstrating longer progression-free survival and overall survival than MRD-positive patients. Sustained MRD negativity is associated with superior outcomes, while loss of MRD negativity is linked to worse prognosis, contributing to MRD status being actively evaluated as a surrogate endpoint for progression-free survival in patients with newly diagnosed multiple myeloma.
• Researchers conducted a global, randomized, open-label, phase 3 trial (IMROZ) in 21 countries, enrolling 446 transplant-ineligible patients with newly diagnosed multiple myeloma aged ≥ 18 years who were randomly assigned 3:2 to receive Isa-VRd/Isa-Rd (n = 265) or VRd/Rd (n = 181).
• Patients in the Isa-VRd arm received intravenous isatuximab at 10 mg/kg weekly in cycle 1, then every 2 weeks, plus subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, and 32, oral lenalidomide 25 mg/d on days 1-14 and 22-35, and oral or intravenous dexamethasone 20 mg/d for four 6-week induction cycles.
• During continuous maintenance, patients received isatuximab 10 mg/kg every 2 weeks (monthly from cycle 18), lenalidomide 25 mg/d on days 1-21, and dexamethasone 20 mg/d once weekly until disease progression or unacceptable adverse events.
• MRD negativity was assessed by next-generation sequencing using the clonoSEQ Assay version 2.0 at 10^-5 and 10^-6 sensitivity thresholds from bone marrow aspirates obtained at baseline, end of induction (month 6), and during maintenance (months 12, 18, 24, and then yearly) from patients with very good partial response or better.
• Analysis evaluated MRD dynamics over time using landmark analyses at predefined time points, with a median follow-up of 59.7 months, assessing cumulative MRD negativity rates; sustained MRD negativity for ≥ 12, ≥ 24, and ≥ 36 months; and conversion rates between MRD-positive and MRD-negative status.

TAKEAWAY:

• At the end of induction (6 months), MRD negativity rates at 10^-5 sensitivity were 49.7% for Isa-VRd/Isa-Rd compared with 25.4% for VRd/Rd, increasing during maintenance to 76.1% compared with 40.0% at 60 months (odds ratio [OR], 4.59).
• Sustained MRD negativity for ≥ 24 months was achieved in 35.8% of patients receiving Isa-VRd/Isa-Rd compared with 13.3% receiving VRd/Rd (OR, 3.65), with rates for ≥ 12 months of 46.8% compared with 24.3% (OR, 2.73).
• Conversion from MRD negativity at induction to MRD positivity during maintenance occurred in substantially fewer patients with Isa-VRd/Isa-Rd than with VRd/Rd (5.6% vs 26.9% at 24 months and 12.3% vs 34.8% at 36 months).
• Among patients who converted from MRD negative to MRD positive at any timepoint, time to progression was prolonged with Isa-VRd/Isa-Rd vs VRd/Rd (hazard ratio [HR], 0.275; P = .0041), with similar benefit observed for conversion after induction (HR, 0.236; P = .0036).

IN PRACTICE:

“Our findings on the degree of MRD negativity and MRD-negative CR benefit achieved during induction and maintenance by patients receiving Isa-VRd/Isa-Rd vs VRd/Rd extend the IMROZ primary analyses and further support Isa-VRd as standard of care for frontline treatment of transplant-ineligible patients with [newly diagnosed multiple myeloma],” the authors of the study wrote.

SOURCE:

The study was led by Robert Z. Orlowski, MD, PhD, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center in Houston, and Philippe Moreau, MD, Department of Hematology, University Hospital Hôtel-Dieu in Nantes, France. It was published online on June 4 in Blood.

LIMITATIONS:

The study’s MRD assessment protocol required bone marrow sampling only from patients achieving very good partial response or better, which may have excluded patients with lower response levels who were unlikely to achieve MRD negativity, potentially introducing selection bias. The analysis of sustained MRD negativity for ≥ 36 months was limited by immature data and insufficient follow-up duration at the time of analysis. Landmark analyses, while designed to mitigate lead-time bias inherent to MRD conversion analyses, may still contain other potential biases that could affect interpretation of outcomes. The study excluded patients aged > 80 years and those with Eastern Cooperative Oncology Group performance status > 2 or estimated glomerular filtration rate < 30 mL/min per 1.73 m², limiting generalizability to these populations.

DISCLOSURES:

Sanofi provided funding for this study. Orlowski disclosed receiving consulting fees from multiple pharmaceutical companies including AbbVie, Adaptive Biotechnologies, Bristol Myers Squibb/Celgene, GSK, Sanofi, and Takeda, among others; holding stocks in Asylia Therapeutics; and institutional funding from CARsgen, Exelixis, Heidelberg Pharma, and Sanofi. Moreau disclosed receiving honoraria from and serving in consulting/advisory roles with Amgen, Bristol Myers Squibb/Celgene, GSK, Janssen, Pfizer, Sanofi, and Takeda. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.