ATLANTA—Adding an anti-CD38 monoclonal antibody (isatuximab [Sarclisa]) to lenalidomide/bortezomib/dexamethasone induction therapy for newly-diagnosed multiple myeloma (NDMM) significantly improved minimal residual disease (MRD) negativity according to results of the Phase III GMMG-HD7 trial.
The trial’s findings were reported at the American Society of Hematology 2021 meeting here.
“I expect this to be standard-of-care induction therapy for transplant-eligible NDMM patients by 2024,” Hartmut Goldschmidt, MD, of University Hospital Heidelberg and the National Center for Tumor Diseases, also in Heidelberg, Germany, told BreakingMED.
Lenalidomide/bortezomib/dexamethasone (RVd) is the current standard of care, and the add-on isatuximab regimen is “the first to challenge the standard of care,” he added.
Isatuximab is currently FDA approved in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and in combination with carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.
Goldschmidt predicted that add-on isatuximab induction therapy is likely to be introduced into clinical practice in the U.S. before it gains acceptance in Europe because European regulators exert tighter control over which drugs can be used in combination.
During an ASH press briefing, Goldschmidt said there have “been ongoing discussions between colleagues on the myeloma group with the FDA about how we can approach the [MRD] data and predict overall survival and progression-free survival. This discussion is not finished.” He noted that the FDA does not accept MRD negativity as a surrogate for response in patients with multiple myeloma.
Laurie Sehn, MD, of British Columbia Cancer Centre for Lymphoid Cancer and The University of British Columbia, said the GMMG-HD7 results were one of several trials that underline the shift from chemotherapy to immunotherapy, an evolution that she characterized as transformative, especially, “for someone like me who has been steeped in chemotherapy.”
Goldschmidt and colleagues enrolled 662 newly diagnosed patients at 67 medical centers in Germany and randomized them 1:1 to induction therapy with isatuximab plus RVd or RVd alone for 18 weeks. The median age of patients was 59 in the isa-RVd arm and 60 in the control group. In both arms, 60% of the patients were men and less than 7% had renal impairment at baseline. More than half of the patients in each arm were Revised International Staging System (R-ISS) stage II.
After 18 weeks, “50.1% of the Isa-RVd patients had improved MRD negativity versus 35.6% of RVd patients (P<0.001). These are the first Phase III results to demonstrate superiority to RVd,” Goldschmidt said.
“On multivariate analyses, including treatment arm, R-ISS, performance status, renal impairment, age, and sex, treatment with Isa-RVd (versus RVd) remained the only significant predictor for increased MRD negativity after induction (OR=1.82, 95% CI: 1.33-2.49, P<0.001),” he said.
Moreover, although at 18 weeks “rates of complete response after induction did not yet differ between the RVd versus Isa-RVd arms (21.6% versus 24.2%), the rate of very good partial response or better (≥VGPR) was significantly higher in the Isa-RVd arm (60.5% versus 77.3%, P<0.001). The rates of progressive disease were 4.0% (RVd) versus 1.5% (Isa-RVd),” he noted.
There was no apparent difference in response among subgroups, nor in the rate of adverse events. The most common “AE (grade ≥3) by system organ class (SOC) for RVd versus Isa-RVd were: …blood and lymphatic system disorders: 16.8% versus 25.8% (P=0.006); infections and infestations: 10.4% versus 13.0% (P=0.33); and nervous system disorders: 10.1% versus 8.5% (P=0.50). Rates of serious AE (SAE, any grade) on induction were similar between RVd and Isa-RVd (36.3% versus 34.8%, P=0.75).”
There were eight deaths in the control group and four in the Isa-RVd arm during induction.
Goldschmidt noted that the trial is “ongoing, including analyses post autologous transplantation, which is followed by a second randomization to compare the efficacy of the addition of Isa to lenalidomide maintenance.”
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In a randomized phase III trial, the addition of isatuximab to standard-of-care induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients resulted in significantly better minimal residual disease (MRD) negativity.
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Be aware that this activity describes an off-label use of isatuximab.
Peggy Peck, Editor-in-Chief, BreakingMED™
The GMMG-HD7 Trial was supported by Sanofi.
Goldschmidt disclosed consultant agreements or research funding with Takeda, Sanofi, Adaptive Biotechnology, Incyte, GSK, Chugai, Celgene, BMS, Janssen, Johns Hopkins University, MSD, Mundipharma, Dietmar-Hopp-Foundation, Novartis, and Amgen.
Cat ID: 332
Topic ID: 78,332,730,332,468,192,925,331
