Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy in Patients With Newly Diagnosed Multiple Myeloma: The Phase 3 GMMG-HD7 Trial

In patients with newly diagnosed multiple myeloma (NDMM), the use of anti-CD38 monoclonal antibodies (mAbs) enhances the effectiveness of standard treatment protocols.¹ The phase 3 GMMG-HD7 trial (NCT03617731) investigated the effect of isatuximab (Isa) in induction therapy with lenalidomide/bortezomib/dexamethasone (RVd) and in lenalidomide maintenance treatment. The incorporation of the CD38 mAb iIsa into the treatment regimen of RVd for patients with transplant-eligible NDMM successfully achieved the primary objective of minimal residual disease (MRD) negativity in bone marrow following induction therapy (Isa-RVd: 50% vs RVd: 36%.^1,2 This article summarizes the effect of induction therapy with Isa-RVd versus RVd on progression-free survival (PFS), and in a landmark analysis, the impact of MRD negativity on PFS.

Patients with transplant-eligible NDMM were categorized according to the Revised International Staging System (R-ISS) and randomly assigned to receive three 42-day cycles of RVd.^1,2 After the induction therapy, patients underwent stem cell collection using a cyclophosphamide-based regimen, followed by high-dose melphalan (200 mg/m²) and autologous stem cell transplant (ASCT). Subsequently, patients were randomized to receive maintenance therapy with either lenalidomide alone (10 mg/day orally on a continuous basis) or in combination with Isa for a duration of up to 36 months.^1,2 The assessment of MRD negativity from bone marrow samples was conducted using next-generation flow cytometry, which has a sensitivity of 10^-5, without regard to the response rates established by the International Myeloma Working Group. The definition of continued MRD-negativity status was established as MRD negativity remaining from the post-induction phase to the post-intensification phase.² PFS was defined as time from first randomization to disease progression or death from any cause, whichever occurred first.¹ The data cutoff was January 31, 2024.^1,2

Between October 2018 and September 2020, 662 patients were included in the trial. The intention-to-treat analysis comprised 660 patients (Isa-RVd, n=331; RVd, n=329). Baseline characteristics were well balanced between both arms.^1,2 At a median follow-up of 47 months, there were 179 recorded PFS events.¹ The Isa-RVd induction therapy significantly enhanced PFS when compared with RVd. The 3-year PFS rates were 83% for the Isa-RVd group and 75% for the RVd group. This PFS advantage for Isa-RVd over RVd was corroborated by multivariable analysis, which included variables such as R-ISS stage, age, sex, performance status, and renal insufficiency.¹ Analyses of subgroups indicated a consistent PFS benefit for Isa-RVd relative to RVd induction across various clinically relevant baseline categories, including both genders, patients with good performance status, and patients in R-ISS stages I, II, and III, as well as patients with normal and elevated lactate dehydrogenase levels and standard-risk cytogenetics. Conversely, patients with poor performance status and high-risk cytogenetics did not show any benefit at the time of testing.¹

In the respective PFS landmark analyses conducted after induction and intensification, a greater percentage of patients in the Isa-RVd group compared with the RVd group exhibited enhanced rates of MRD negativity and sustained MRD negativity.² PFS was notably extended in patients who achieved MRD negativity, with 3-year PFS rates post-induction therapy recorded as 88% for MRD-negative patients and 71% for patients who are MRD-positive. Within the MRD-negative cohort, PFS outcomes were comparable between the Isa-RVd and RVd treatment arms. However, MRD-positive patients experienced a significantly longer PFS when treated with Isa-RVd compared with RVd.² Furthermore, patients maintaining MRD-negativity status exhibited a marked prolongation of PFS in contrast with patients who did not maintain MRD negativity. The 3-year PFS rates at the end of maintenance therapy were 90% for patients with sustained MRD negativity and 77% for patients without MRD negativity.² Multivariable analyses, which accounted for the induction-treatment arm, essential baseline patient characteristics, and disease risk factors, confirmed the significant prognostic influence of MRD negativity on PFS following the end of induction therapy, as well as the impact of continued MRD negativity on PFS from the initiation of maintenance therapy.²

The addition of Isa to the RVd treatment protocol over an 18-week induction period, followed by ASCT, resulted in a significant and clinically meaningful increase in PFS, independent of the maintenance therapy strategy utilized.¹ A greater number of patients achieved and maintained MRD negativity with the Isa-RVd regimen compared with RVd.² However, the PFS benefit following the attainment and maintenance of MRD negativity was comparable in both treatment groups. In patients who remained positive for MRD, the incorporation of Isa into the RVd regimen demonstrated a significant improvement in PFS compared with RVd alone.²

In April 2024, the FDA’s Oncologic Drugs Advisory Committee (ODAC) decided that the evidence presented in these analyses supports the use of MRD as an accelerated approval endpoint in multiple myeloma clinical trials.³ The ODAC acknowledged that MRD as an endpoint represents a major opportunity for acceleration of drug development in multiple myeloma, especially in the frontline setting.³

References

1. Goldschmidt H, Bertsch U, Pozek E, et al. Isatuximab, lenalidomide, bortezomib and dexamethasone induction therapy for transplant-eligible patients with newly diagnosed multiple myeloma: final progression-free survival analysis of part 1 of an open-label, multicenter, randomized, phase 3 trial (GMMG-HD7). Presented at: 66th ASH Annual Meeting & Exposition. December 7-10, 2024; San Diego, CA. Abstract 769.
2. Mai EK, Salwender H, Hundemer M, et al. Impact of minimal residual disease on progression-free survival in patients with newly diagnosed multiple myeloma treated with isatuximab, lenalidomide, bortezomib and dexamethasone induction therapy in the phase 3 GMMG-HD7 trial. Presented at: 66th ASH Annual Meeting & Exposition. December 7-10, 2024; San Diego, CA. Abstract 364.
3. FDA. Center for Drug Evaluation and Research. Final summary minutes of the Oncologic Drugs Advisory Committee Meeting. April 12, 2024; Silver Spring, MD.