Isatuximab significantly increases the rate of minimal residual disease when added to RVd as induction therapy for newly diagnosed multiple myeloma
According to results of the phase III GMMG-HD7 trial, the addition of the anti-CD38 monoclonal antibody isatuximab to standard induction therapy with lenalidomide, bortezomib, and dexamethasone (RVd) significantly increases the likelihood of obtaining minimal residual disease (MRD) negativity in patients with newly diagnosed, transplant-eligible multiple myeloma (MM). With the isatuximab-based treatment, half of the patients proved to be MRD-negative after induction therapy, while this was only the case for 35.6% of patients treated with RVd alone.
To date, RVd is a recommended first line treatment for patients with newly diagnosed MM (NDMM) who are eligible for an autologous stem cell transplantation (ASCT). In recent years, monoclonal antibodies targeting CD38 have dramatically changed the treatment landscape in MM. Initially these agents were evaluated in the relapsed/refractory setting and in transplant ineligible patients, but these agents are now also being explored as part of induction therapy in patients with transplant-eligible NDMM. One of these anti-CD38 antibodies consists of isatuximab, an agent that is already approved in combination with dexamethasone and either pomalidomide or carfilzomib in the treatment of relapsed/refractory MM. The goal of the phase III GMMG-HD7 trial was to assess whether the addition of isatuximab to induction therapy RVd could improve the rate of MRD-negativity in patients with transplant-eligible NDMM.
Study design
In this multicenter, open-label, phase III trial, patients with transplant-eligible NDMM coming from 67 sites across Germany were randomized to receive three 42-day cycles of RVd (lenalidomide 25 mg/d p.o., d1–14 and d22-35; bortezomib 1.3 mg/m2 s.c. d1, 4, 8, 11, 22, 25, 29, 32; dexamethasone 20 mg/d d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33) with or without isatuximab (10 mg/kg i.v., cycle 1: d 1, 8, 15, 22, 29; cycles 2-3: d 1, 15, 29). Following this induction phase patients underwent an ASCT followed by maintenance therapy with either isatuximab + lenalidomide, or lenalidomide alone. The primary endpoint of the trial was MRD negativity assessed by next-generation flow (NGF, sensitivity x10-5) after induction. Key secondary study objectives included rates of complete response (CR) after induction and safety. The study included a total of 662 patients of whom 660 were eligible for the intent-to-treat analysis and 658 started induction therapy.
Results
Baseline patient and disease characteristics were well-balanced between the two study arms, with a median age of 59 years. High risk cytogenetics were reported in 17.5% of patients in the Isa-RVd arm as compared to 20.1% in the RVd arm. Slightly more patients in the Isa-RVd arm had ISS stage II disease compared to the RVd alone arm (65.9% vs. 56.2%). During the induction phase 35 (10.6%) and 18 (5.4%) patients discontinued treatment in the RVd and Isa-RVd arms (p=0.02), respectively. Among these, 8 (2.4%, RVd) and 7 (2.1%, Isa-RVd) patients discontinued induction due to adverse events (AE). In total 293 (89.1%) and 312 (94.3%) patients in the RVd and Isa-RVd arms, respectively, continued further study treatment after induction.
The study met its primary endpoint with a rate of MRD negativity of 50.1% in the Isa-RVd arm as compared to 35.6% with RVd alone. (OR[95%CI]: 1.83[1.34-2.51]; p< 0.001). This benefit was consistently seen across all clinically relevant subgroups. In addition, patients receiving isatuximab were also significantly more likely to achieve a very good partial response or better (77.3% vs. 60.5%; p< 0.0001) and less likely to show evidence of disease progression (progression rate: 1.5% vs. 4.0%).
Importantly, there was no major difference between the two treatment arms looking at the overall incidence of adverse events (63.6% vs. 61.3%) or serious adverse events (34.8% vs. 36.3%). The most common adverse event with Isa-RVd consisted of leukocytopenia and neutropenia (26.4% vs. 9.1% with RVd alone).
Conclusions
The GMMG-HD7 trial met its primary endpoint making it the first phase III trial to demonstrate superiority of MRD negativity rates after induction by adding a CD38-monoclonal antibody to RVd. There was no increased risk of SAE or early discontinuation in patients treated with Isa-RVd compared to RVd. The study is still ongoing and will assess next the impact of isatuximab-RVd vs. RVd induction therapy after autologous stem cell transplantation, as well as the drug’s potential effects when used as part of the maintenance regimen with lenalidomide.
Reference
Goldschmidt H, et al. Addition of Isatuximab to Lenalidomide, Bortezomib and Dexamethasone as Induction Therapy for Newly-Diagnosed, Transplant-Eligible Multiple Myeloma Patients: The Phase III GMMG-HD7 Trial. Presented at Ash 2021; Abstract 463.
