Isatuximab-Rd vs. Rd induction, followed by isa-R vs. R maintenance in very elderly patients with NDMM: results of AGMT-MM04

At ASH 2025, Prof Heinz Ludwig, haematologist at the Wilhelminen Cancer Research Institute in Vienna presented a poster describing the results of a randomized phase II AGMT-MM04 study. This trial evaluated the efficacy and safety of isatuximab plus lenalidomide–dexamethasone (Isa-Rd) versus lenalidomide–dexamethasone (Rd) alone in very elderly patients with newly diagnosed multiple myeloma (NDMM).

The study enrolled 137 transplant-ineligible patients aged ≥70 years with NDMM. Patients were randomized to receive either eight cycles of Isa-Rd induction followed by isatuximab plus lenalidomide maintenance for 24 cycles, or Rd induction followed by lenalidomide maintenance alone. The total planned treatment duration was 32 months. The primary endpoint was minimal residual disease (MRD) negativity after induction, with secondary endpoints including progression-free survival (PFS), overall survival (OS), response rates, cytogenetic subgroup analyses, and safety. MRD was centrally assessed using next-generation flow cytometry at sensitivities of 10⁻⁵ and 10⁻⁶.

After induction, overall response rates were similar between arms, however, Isa-Rd achieved significantly higher rates of very good partial response (VGPR) or better compared with Rd alone. At the end of induction, MRD negativity was markedly higher in the Isa-Rd arm (38%) compared with Rd, at both sensitivity thresholds. These results translated into a clinically meaningful improvement in PFS, with a median PFS advantage of approximately 18 months favoring Isa-Rd. A trend toward improved OS was observed with Isa-Rd, although this was not statistically significant at the time of analysis.

MRD negativity was strongly associated with prolonged PFS regardless of assay sensitivity. Patients with high-risk cytogenetics had an inferior PFS. However, MRD negativity rates were comparable across cytogenetic risk groups, suggesting that Isa-Rd is effective even in biologically high-risk disease. Notably, early clearance of circulating tumor cells after one treatment cycle correlated with significantly improved PFS, highlighting a potential early predictive biomarker.

Safety profiles were comparable between treatment arms, with no significant increase in hematologic toxicity or infections associated with isatuximab.