The addition of isatuximab (Sarclisa) to the triplet of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) achieved superior minimal residual disease (MRD) negativity rates versus standard therapy with RVd alone as induction treatment in transplant-eligible patients with newly diagnosed multiple myeloma, according to results of the phase 3 GMMG-HD7 clinical trial presented at the 2021 ASH Annual Meeting and Exposition.
The study met its primary end point. Of the 331 patients assigned to isatuximab plus RVd, 50.1% had no MRD at the end of induction therapy versus 35.6% among the 329 assigned to RVd alone, a difference that was statistically significant (P <.001). A consistent benefit with regard to MRD negativity at the end of induction favoring the isatuximab combination regimen was observed across all prespecified subgroups.
“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 for newly diagnosed, transplant-eligible multiple myeloma,” said lead investigator Hartmut Goldschmidt, MD, President, German-speaking Myeloma Multicenter Group, and Head, Multiple Myeloma Program, Heidelberg University Hospital and National Center of Tumor Diseases, Germany. “The addition of isatuximab had no significant impact on the safety profile or dose intensity of RVd.”
The RVd regimen has long been the preferred first-line therapy for transplant-eligible patients with newly diagnosed multiple myeloma. Isatuximab was evaluated in combination with RVd with the goal of optimizing the depth of response before transplant, improving patient outcomes.
Isatuximab is targeted to a specific epitope on CD38, which is uniformly expressed on myeloma cells.
In March 2020, the FDA approved isatuximab, in combination with pomalidomide (Pomalyst) and dexamethasone, for adults with multiple myeloma who had received ≥2 previous therapies, including lenalidomide and a proteasome inhibitor. In March 2021, the FDA approved isatuximab plus carfilzomib (Kyprolis) and dexamethasone for adults with relapsed or refractory multiple myeloma who had previously received 1 to 3 lines of therapy.
The GMMG-HD7 study is the first phase 3 clinical trial to evaluate the addition of isatuximab to RVd for the induction and maintenance treatment of patients with newly diagnosed multiple myeloma eligible for high-dose therapy and autologous stem-cell transplantation.
The study randomized 662 patients in a 1:1 ratio to isatuximab plus RVd or RVd. Induction therapy was given in three 6-week cycles. After high-dose therapy and autologous stem-cell transplantation, patients will enter the maintenance phase of the trial and will be re-randomized to isatuximab plus lenalidomide or to lenalidomide alone for 4-week cycles. Treatment will be given for 3 years or stopped in patients with progressive disease.
The primary end point of the trial is MRD negativity at the end of induction treatment. Secondary end points include complete response after induction and safety.
The data cutoff at the time of the presentation was April 2021. The study is still evaluating patients following the second randomization in the maintenance phase of the trial, Dr Goldschmidt said.
Patient baseline characteristics were well-balanced between the 2 treatment arms and the median age was 58 years, ranging from 26 to 70 years. Approximately 6% of patients had renal impairment at baseline and approximately 19% had high-risk cytogenetics.
In the investigative arm, 23.3% had stage I disease, 65.9% had stage II disease, 8.5% had stage III disease, and 2.4% had disease “not classified.” In the control arm, the corresponding rates for stage I, II, III, and “not classified” were 30.1%, 56.2%, 7.9%, and 5.8%, respectively.
The addition of isatuximab to RVd did not significantly alter the safety profile or dose intensity of RVd. Almost two-thirds (63.6%) of patients who received isatuximab plus RVd had an any-grade adverse effect (AE) versus 61.3% of those who received RVd alone. Serious AEs were reported in 34.8% and 36.3% of patients, respectively. Four (1.2%) deaths occurred in the isatuximab plus RVd arm compared with 8 (2.4%) in the RVd-alone arm.
Slightly more than one-fourth (26.4%) of patients in the combination arm had leukocytopenia or neutropenia versus 9.1% of those in the control arm. Four patients in the isatuximab plus RVd arm reported infusion-related reactions; these data were not applicable for the RVd arm.
“Isatuximab plus RVd showed a manageable and consistent safety profile in patients with transplant-eligible, newly diagnosed multiple myeloma with no new safety signals observed,” Dr Goldschmidt noted.
Other phase 3 trials are evaluating the efficacy of isatuximab for the treatment of transplant-eligible and -ineligible patients with newly diagnosed multiple myeloma. The drug is being investigated in combination with RVd and carfilzomib, lenalidomide, and dexamethasone.
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