Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma: Final Part 1 Analysis of the GMMG-HD7 Trial

Abstract

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.

FIG 1.

Analyses of PFS from part 1 of the GMMG-HD7 trial comparing Isa-RVd with RVd induction. (A) Kaplan-Meier estimates for PFS from the first random assignment. PFS rates at 3 and 4 years were 83% (95% CI, 79 to 87) and 76% (95% CI, 71 to 81) with Isa-RVd versus 75% (95% CI, 70 to 80) and 69% (95% CI, 63 to 74) with RVd, respectively. (B) Subgroup analyses for PFS from the first random assignment. (C) Multivariable model on PFS. (D) Weighted risk set estimator analysis for PFS accounting for second random assignment. Estimated PFS rates at 3 and 4 years were 84% (95% CI, 79 to 89) and 74% (95% CI, 68 to 81) with Isa-RVd versus 73% (95% CI, 67 to 79) and 64% (95% CI, 56 to 71) with RVd, respectively. The numbers at risk counts are raw counts of the 331 and 329 patients who were randomly assigned. d, dexamethasone; HR, hazard ratio; Isa, isatuximab; ISS, International Staging System; LDH, lactate dehydrogenase; PFS, progression-free survival; R, lenalidomide; R-ISS, Revised International Staging System; V, bortezomib.

FIG 2.

Impact of MRD status on PFS in part 1 of the GMMG-HD7 trial. (A) PFS from end of induction with respect to MRD status. Estimated 3-year PFS rates were 88% (95% CI, 85 to 92) in the Isa-RVd group and 71% (95% CI, 66 to 77) in the RVd group. (B) PFS from start of maintenance with respect to MRD status at the end of transplant. Estimated 3-year PFS rates after transplant were 87% (95% CI, 83 to 91) in the Isa-RVd group and 73% (95% CI, 66 to 81) in the RVd group. (C) PFS from end of induction with respect to induction treatment arm and MRD status. (D) PFS from start of maintenance with respect to induction treatment arm and MRD status at the end of transplant. (E) PFS from start of maintenance with respect to continued MRD–.^a Estimated 3-year PFS rates from maintenance start were 90% (95% CI, 86 to 94) in the Isa-RVd group and 77% (95% CI, 72 to 83) in the RVd group. (F) PFS from start of maintenance with respect to induction treatment arm and continued MRD–.^a The median time from random assignment to MRD measurements (after induction) was 4.57 and 4.47 months in the Isa-RVd and RVd arms, respectively, and the corresponding post-transplant time from random assignment to MRD measurements was 9.72 and 9.81 months, respectively. The median time between continued MRD measurements (between end of induction and end of transplant) was 5.04 and 5.17 months, respectively. ^aContinued MRD– was defined as MRD– persisting from end of induction to post-transplant. d, dexamethasone; HR, hazard ratio; Isa, isatuximab; MRD, minimal residual disease; PFS, progression-free survival; R, lenalidomide; V, bortezomib.