Previously, addition of isatuximab (Isa) to standard-of-care lenalidomide-bortezomib-dexamethasone (RVd) in transplant-eligible patients with newly diagnosed multiple myeloma in the GMMG-HD7 trial (ClinicalTrials.gov identifier: NCT03617731) resulted in a significant increase of minimal residual disease negativity (MRD-) rates after induction therapy. A total of 662 patients were randomly assigned to receive induction therapy with Isa-RVd (n = 331) or RVd (n = 329), followed by single or tandem autologous stem-cell transplant and second random assignment to maintenance with lenalidomide alone or Isa-lenalidomide. We report updated results for part 1 from first random assignment to post-transplant. As of January 31, 2024, MRD- rates continued to deepen after transplant (66% Isa-RVd v 48% RVd). Isa-RVd induction therapy significantly prolonged progression-free survival (PFS) compared with RVd regardless of maintenance therapy (hazard ratio, 0.70 [95% CI, 0.52 to 0.95]; P = .0184). Weighted risk set estimator analysis accounting for second random assignment followed by maintenance with only lenalidomide confirmed a statistically significant benefit for Isa-RVd followed by lenalidomide maintenance versus RVd followed by lenalidomide maintenance (stratified weighted log-rank test P = .016). In conclusion, after 18-week induction therapy followed by transplant without consolidation therapy, adding Isa to RVd resulted in a significant PFS benefit, regardless of maintenance strategy.