Phase 3 GMMG-HD7 Trial: Assessing the Impact of Isatuximab on MRD Negativity and PFS in Multiple Myeloma

The phase 3 GMMG-HD7 trial (NCT03617731) evaluated the combination of isatuximab (Isa, Sarclisa; Sanofi Genzyme), an anti-CD38 monoclonal antibody, with the standard induction therapy of lenalidomide (Revlimid; Celgene), bortezomib (Velcade; Millennium: The Takeda Oncology Company), and dexamethasone (RVd) in patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation (ASCT). Isa has demonstrated efficacy in multiple myeloma through various mechanisms, and it has been approved by the FDA for use in combination with carfilzomib (Kyprolis; Onyx Pharmaceuticals, Inc), dexamethasone, and pomalidomide (Pomalyst; Bristol Myers Squibb) in patients with relapsed or refractory disease.^1,2

At the 66th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California, Elias K. Mai, MD, explained that the GMMG-HD7 trial aimed to explore the impact of MRDneg and continued MRDneg on progression-free survival (PFS).¹

“Isa is an anti‐CD38 monoclonal antibody, which exerts anti-myeloma effects via several known mechanisms,” said Mai, a specialist in internal medicine, hematology and oncology at Medicine V, University Hospital Heidelberg in Heidelberg, Germany, during the ASH presentation. “In this update, we will present PFS data with a median follow up of 48 months from the first randomization.”¹

A vector representation of multiple myeloma cells. Image Credit: © sovova - stock.adobe.com

The trial enrolled 662 patients who were randomized to receive either Isa-RVd or RVd induction therapy, followed by ASCT. Patients who achieved less than a complete response or had high-risk disease could proceed to consolidation therapy. After ASCT, patients were again randomized to receive maintenance therapy with either lenalidomide alone or in combination with Isa for up to 3 years.^1,2

At the end of induction therapy, patients receiving Isa-RVd had a significantly higher MRDneg rate (66%) compared to those on RVd alone (48%). Furthermore, patients with continued MRDneg rates on PFS from start of maintenance therapy had higher rates in the Isa-RVd group (53%) compared to RVd (38%). These findings suggest that the addition of Isa enhances MRDneg rates during induction and post-transplantation, according to Mai.^1,2

“MRD was assessed in the trial by next generation flow cytometry from bone marrow aspirates, independent of International Myeloma Working Group response rates. MRD status was reported at a 10^-5 sensitivity level, and we defined continued MRD status as MRDneg persisting from post-induction to post-transplant,” Mai said. “MRDneg rates also continue to deepen over time post-transplant.”¹

Notably, the benefit of MRDneg status on PFS was similar regardless of the treatment arm, indicating that Isa-RVd improves MRDneg rates without compromising PFS outcomes when compared to RVd alone, Mai explained.¹

When examining the impact of MRDneg status at the start of maintenance therapy, the study found a 58% reduction in the risk of progression or death for patients who were MRDneg. Moreover, patients who remained MRD-positive after induction but received Isa-RVd showed a longer PFS compared to those on RVd alone, highlighting the advantage of adding Isa for patients with persistent MRD positivity. The PFS benefit was also consistent across most clinically relevant subgroups, particularly in patients who achieved continued MRDneg status.^1,2

The multivariable analysis reinforced the importance of MRDneg status, both at the end of induction and during maintenance, as a significant prognostic factor for PFS. Other factors, such as age and cytogenetic risk, were also found to influence PFS outcomes, according to Mai. The results of this trial suggest that the combination of Isa with RVd induction therapy improves MRDneg rates and translates into long-term benefits, particularly for patients who maintain MRDneg status throughout treatment.^1,2

“Isa-RVd is the first regimen in a phase 3 trial to demonstrate deep and rapid response reflected by statistically significant MRDneg benefit at the end of induction, and also post-transplant,” Mai said. “Further deepening of MRD response was observed post-transplant and there was a consistent benefit for MRD negativity for patients treated with Isa-RVd across most subgroups. GMMG-HD7 is the first phase 3 trial to show that an 18-week initial induction quadruplet regimen with Isa without consolidation after transplant allows for MRD negativity response, translating into significant long-term benefits, regardless of subsequent maintenance therapy.”¹

The trial's ongoing follow-up will provide further insights, according to Mai, particularly regarding the second randomization and the impact of different maintenance strategies on long-term outcomes.¹

“The follow up is ongoing, and the next readout from the trial will focus on part 2, which is PFS from second randomization, looking at the 2 different maintenance strategies,” Mai said. “As you're all aware, this is the only trial that has the second randomization to further elucidate the effect of the addition of an anti-CD38 monoclonal antibody to another line.”¹

REFERENCES

1. Mai EK. 653. Multiple Myeloma: Clinical and Epidemiological: Advancing Minimal Residual Disease (MRD): Detection, Impact on Prognosis and Treatment Decisions. Presented at: 66th ASH Annual Meeting and Exposition; San Diego, California; December 7-10, 2024.

2. Mai EK, Salwender H, Hundemer M, et al. 364 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 TrialClinically Relevant Abstract. American Society of Hematology. 2024. Accessed December 7, 2024. https://ash.confex.com/ash/2024/webprogram/Paper206409.html