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Isatuximab-Containing Induction Therapy for Multiple Myeloma Increases Measurable Residual Disease Negativity


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For the first-line treatment of newly diagnosed multiple myeloma, the percentage of patients achieving measurable residual disease (MRD, previously called minimal residual disease) negativity was significantly greater when the anti-CD38 monoclonal antibody isatuximab was added to a standard three-drug induction regimen, as compared with standard therapy alone, in the first primary analysis of the phase III GMMG-HD7 trial. This study—one of the first in myeloma to use MRD as an endpoint—was presented at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition by Hartmut ­Goldschmidt, MD, of the Heidelberg University Hospital and National Center of Tumor Diseases Heidelberg, Germany.1

“This is the first phase III trial to successfully challenge a standard of care (RVd [lenalidomide/bortezomib/dexamethasone]) that is broadly used in the United States and Europe. Isatuximab plus the combination regimen of RVd is the first to show superiority vs RVd alone in a phase III trial,” Dr. Goldschmidt said. “The MRD negativity rate of 50.1%, reached with 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.”


The MRD negativity rate of 50.1%, reached with isatuximab plus RVd at the end of induction, is the highest described to date in a randomized trial setting….
— Hartmut ­Goldschmidt, MD

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The study randomly assigned newly diagnosed transplant-­eligible patients to receive either RVd alone or in combination with isatuximab. After induction with isatuximab plus RVd, MRD negativity in the bone marrow at a cutoff of 1 × 10–5 (assessed by next-generation flow) was achieved by 50.1% of patients, compared with 35.6% of patients after treatment with RVd alone (odds ratio [OR] = 1.83; 95% confidence interval = 1.34–2.51; P < .001), reported Dr. Goldschmidt.

Isatuximab has been approved in the United States, Europe, and many other countries in combination with pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma who have had at least two prior therapies and in combination with carfilzomib and dexamethasone in patients treated with one to three prior lines. The current trial assessed the use of isatuximab as part of the first-line treatment for newly diagnosed, transplant-eligible patients up to age 70.

Isatuximab binds to a specific epitope on myeloma cells and thereby activates the immune system to eliminate the tumor cells via multiple well-described immune effector mechanisms. “The idea is that if the immune system is being activated by isatuximab, treatment of myeloma will be more effective,” Dr. Goldschmidt explained.

GMMG-HD7 Trial Details

GMMG-HD7 is the first phase III study to evaluate MRD negativity at the end of induction in transplant-eligible newly diagnosed patients. About 19% of patients had high-risk cytogenetics. The baseline characteristics in the arms were balanced, except more of the ­experimental arm had Revised International Staging System (R-ISS) stage II disease (66% vs 56%) and ­correspondingly less R-ISS stage I disease (23% vs 30%). The median age of patients was 58 (range = 26–70 years).

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 according to 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 to 3 on days 1, 15, and 29 (cycle length = 42 days).

On induction, 11% of the RVd arm and 5% of the isatuximab-plus-RVd arm discontinued treatment; discontinuation was due to an adverse event in about 2% of each arm. Approximately 89% of the RVd arm and 94% of the isatuximab-plus-RVd arm continued treatment after induction. A second randomization is being done for maintenance to lenalidomide alone or in combination with isatuximab.

In regard to MRD negativity status, all prespecified subgroups benefited from the addition of isatuximab, the study investigators reported. Rates of very good partial response or better were significantly higher with isatuximab (60.5% vs 77.3%; P < .001). 

“The addition of isatuximab had no significant impact on the safety profile or dose intensity of RVd,” noted Dr. Goldschmidt. Overall adverse events and serious adverse events were similar between the arms, but neutropenia/leukocytopenias were expectedly more frequent with isatuximab plus RVd (26%) than with RVd alone (9%); this did not translate to higher rates of infections during therapy (13.0% with isatuximab/RVd, 10.4% with RVd alone). The percentages of patients discontinuing treatment due to an adverse event were low (2.1% with isatuximab/RVd, 2.4% with RVd alone) and similar between the treatment arms. 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 multiple myeloma, first noting the technology has come a long way over the past decade. “We now have techniques with a sensitivity of 10–6 and standardization of sequencing techniques; therefore, there is a benefit to analyzing MRD negativity. It’s an ongoing discussion among myeloma specialists and the FDA as to how to incorporate MRD as an endpoint in clinical trials.”

“In my view, MRD assessment is the future of measuring efficacy for multiple myeloma treatment,” Dr. Goldschmidt said, adding that “imaging will continue to be important, too. I believe MRD negativity will prove to be a very good marker of prognosis in myeloma.”

The trial is continuing and will next assess the impact of isatuximab plus RVd vs RVd induction therapy after autologous stem cell transplantation, as well as the drug’s benefit as an add-on therapy to lenalidomide in the maintenance setting. 

DISCLOSURE: Dr. Goldschmidt has served on advisory boards for Adaptive Biotechnology, Amgen, BMS, Celgene, Janssen, Sanofi, and Takeda; and has received grants and/or investigational medicinal product from Amgen, BMS, Celgene, Chugai, Dietmar-Hopp Foundation, Janssen, Johns Hopkins University, and Sanofi; research support from Amgen, BMS, Celgene, Chugai, Janssen, Incyte, Molecular Partners, Merck Sharp & Dohme, Sanofi, Mundipharma GmBH, Takeda, and Novartis; and honoraria from Amgen, BMS, Celgene, Chugai, GlaxoSmithKline, Janssen, Novartis, and Sanofi.

REFERENCE

1. Goldschmidt H, Mai EK, Nievergall E, et al: Addition of isatuximab to lenalidomide, bortezomib and dexamethasone as induction therapy for newly diagnosed, transplant-eligible multiple myeloma patients. 2021 ASH Annual Meeting & Exposition. Abstract 463. Presented December 12, 2021.

 


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