The addition of isatuximab to the triplet of lenalidomide, bortezomib, and dexamethasone (RVd) achieved superior minimal residual disease (MRD) rates versus standard therapy with the RVd regimen alone as induction treatment in transplant-eligible patients with newly diagnosed multiple myeloma, according to results of a phase 3 clinical trial1 presented at the 2021 American Society of Hematology annual meeting.
The study met its primary end point. Of the 331 patients who received isatuximab plus RVd, 50.1% had no MRD at the end of induction therapy versus 35.6% among the 329 patients who received RVd alone (P <.001). A consistent benefit favoring the isatuximab combination regimen was observed across all clinically relevant patient subsets.
“This is the highest MRD negativity described to date in a randomized phase 3 trial setting for newly diagnosed, transplant-eligible patients with multiple myeloma,” said lead investigator Hartmut Goldschmidt, MD, University Hospital Heidelberg 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 regimen for first-line treatment of 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 and improving patient outcomes.
Isatuximab is targeted to a specific epitope on CD38, which is uniformly expressed in myeloma cells.
In March 2020, the FDA approved isatuximab, in combination with pomalidomide 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 and dexamethasone for adults with relapsed or refractory multiple myeloma who have 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 who are eligible for high-dose therapy and autologous stem-cell transplant (ASCT).
The study randomized 662 patients in a 1:1 ratio to isatuximab plus RVd or to RVd. Induction therapy was given in three 6-week cycles. After high-dose therapy and ASCT, 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 meeting was April 2021. The study is still evaluating patients after the second randomization in the maintenance phase of the trial, Dr Goldschmidt said.
Patient baseline characteristics were well-balanced between the 2 treatment arms (median age, 59.5 years; range, 26-70 years). Most patients did not have renal impairment at baseline, nor did they have high-risk cytogenetics.
In the investigative arm, 23.3% of patients 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 the dose intensity of RVd. Almost two-thirds (63.6%) of patients who received isatuximab plus RVd had an any-grade adverse effect versus 61.3% of those who received RVd alone. Serious adverse events 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-quarter (26.4%) of patients in the combination arm had leukocytopenia or neutropenia versus 9.1% of those in the control 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.
Isatuximab is being studied in combination with other multiple myeloma treatments (RVd and carfilzomib, lenalidomide, and dexamethasone) in phase 3 clinical trials for the treatment of transplant-eligible and -ineligible patients with newly diagnosed multiple myeloma.
Reference
- 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: the phase III GMMG-HD7 trial. Blood. 2021;138(suppl 1):Abstract 463.