For the first-line treatment of newly diagnosed, transplant-eligible patients with multiple myeloma, the achievement of measurable residual disease (MRD) negativity was significantly greater when the anti-CD38 monoclonal antibody isatuximab was added to the standard three-drug induction regimen of lenalidomide/bortezomib/dexamethasone (RVd) vs RVd alone. These findings come from the first primary analysis of the phase III GMMG-HD7 trial—which is one of the first pivotal trials to use MRD as an endpoint—and were presented by Hartmut Goldschmidt, MD, and colleagues at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 463).

“This is the first phase III trial to successfully challenge a standard of care that is broadly used in the United States and Europe, and isatuximab/RVd is the first regimen to show superiority vs RVd [alone] in a phase III trial,” said Dr. Goldschmidt, of the Heidelberg University Hospital and National Center of Tumor Diseases Heidelberg in Germany.

“The MRD negativity rate of 50.1%, reached by isatuximab plus RVd at the end of induction, is the highest described to date in a randomized trial setting…Our results support this treatment as a new standard of care in transplant-eligible patients with newly diagnosed myeloma,” Dr. Goldschmidt said.

Hartmut Goldschmidt, MD

The study randomly assigned newly diagnosed, transplant-eligible patients with multiple myeloma to receive RVd alone or RVd plus isatuximab. After induction with RVd/isatuximab, MRD negativity in the bone marrow at a sensitivity of 10^-6 was achieved by 50.1% of patients in the experimental arm, compared to 35.6% of patients treated with RVd alone (odds ratio [OR] = 1.83, P < .001), reported Dr. Goldschmidt.

Isatuximab is approved in the United States, Europe, and many other countries in combination with either pomalidomide or carfilzomib (and dexamethasone) for previously treated patients with multiple myeloma. The current trial assessed its use as part of the first-line treatment for newly diagnosed, transplant-eligible patients up to 70 years of age.

Isatuximab is thought to have an immunostimulatory effect on the tumor, which may be driving the benefit. 

“The idea is that if the immune system is stimulated by isatuximab, treatment of myeloma will be more effective,” explained Dr. Goldschmidt.

GMMG-HD7 Details

GMMG-HD7 is the first phase III study to evaluate MRD negativity at the end of induction in transplant-eligible newly diagnosed patients with multiple myeloma. The arms were balanced, except more patients in the experimental arm had stage II disease (66% vs 56%) and fewer had stage I disease (23% vs 30%). Around 19% of patients had high-risk cytogenetics. The median age was approximately 60 years old.

The study randomly assigned 662 newly diagnosed patients from 67 medical centers in Germany to three cycles (18 weeks total) of isatuximab plus RVd or RVd alone. RVd was administered per standard treatment; isatuximab was given at 10 mg/kg intravenously in cycle 1 on days 1, 8, 15, 22, and 29, and in cycles 2 and 3 on days 1, 15, and 29.

On induction, 11% of patients in the RVd arm and 5% in the isastuximab/RVd arm discontinued treatment; for about 2% of each arm, this was due to an adverse event. Approximately 90% of patients in the RVd arm and 94% in the isatuximab/RVd arm continued on treatment after induction. A second random assignment is being done for maintenance to lenalidomide alone or with isatuximab.

In addition to meeting the trial’s primary endpoint for MRD negativity in the bone marrow, patients receiving isatuximab were significantly more likely to achieve a very good partial response and less likely to show evidence of disease progression. The researchers also found no differences among subgroups, suggesting all patients benefit from the addition of isatuximab to RVd.

“The addition of isatuximab had no significant impact on the safety profile or dose intensity of RVd,” said Dr. Goldschmidt. Overall adverse events and serious adverse events were similar between the arms, but neutropenia/leukocytopenias were more frequent with isatuximab/RVd (26% vs 9%). Percentages of patients discontinuing treatment due to an adverse event were similar. No new safety signals were observed. 

Emerging Importance of MRD Negativity

In a press briefing, Dr. Goldschmidt elaborated on the use of MRD for assessing response in myeloma, first noting that the technology has come a long way over the past decade.

“Now we have techniques with sensitivity of 10^-6 and sequencing techniques are standardized, therefore, there’s a benefit in analyzing MRD negativity. It’s an ongoing discussion among myeloma specialists and the U.S. Food and Drug Adminisreation: how to incorporate MRD as an endpoint in clinical trials.”

“In my view, MRD is the future of myeloma,” he commented, but added imaging will continue to be important. “I believe that MRD negativity will prove to be a very good marker of prognosis in myeloma.”

The ongoing trial will next assess the impact of isatuximab/RVd vs RVd induction after autologous stem cell transplantation, as well as the drug’s potential benefit as an add-on to lenalidomide as maintenance therapy.

Disclosure: For full disclosures of the study authors, visit ash.confex.com.