High MRD Negativity Rates Shown With Isatuximab/RVd in Transplant-Eligible, Newly Diagnosed Myeloma

Hartmut Goldschmidt, MD

Results from the phase 3 GMMG-HD7 trial, show that minimal residual disease (MRD) rates were superior when isatuximab (Sarclisa) was added to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Isa-RVd) as indication therapy compared with RVd alone in patients with transplant-eligible newly diagnosed multiple myeloma.¹

The results of the study, which were presented during the 2021 ASH Annual Meeting, showed that patients who received Isa-RVd (n = 331) achieved a MRD negativity rate of 50.1% at the end of induction therapy vs 35.6% in those who were given RVd alone (n = 329; odds ratio, 1.83; 95% CI, 1.34-2.51; P < .001). Consistent benefit favoring the isatuximab regimen was observed across all clinically relevant subsets.

“This is the highest MRD negativity [rate] described to date in a randomized phase 3 trial setting [for newly diagnosed, transplant-eligible multiple myeloma]," lead study author Hartmut Goldschmidt, MD, of University Hospital Heidelberg and National Center of Tumor Diseases, said during a presentation on the data. “The addition of isatuximab had no significant impact on the safety profile or dose intensity of RVd.”

RVd has long been considered the standard preferred first-line regimen for patients with transplant-eligible, newly diagnosed multiple myeloma. It is important that efforts are made to maximize treatment response before transplant to improve outcomes in these patients.

Isatuximab was designed to target a specific epitope on CD38, which is highly and uniformly expressed in myeloma cells. In March 2020, the FDA approved isatuximab for use in combination with pomalidomide (Pomalyst) and dexamethasone for use in adult patients with multiple myeloma who had received 2 or more prior therapies, including lenalidomide (Revlimid) and a proteasome inhibitor.² The following year, in March 2021, the regulatory agency approved isatuximab plus carfilzomib (Kyprolis) and dexamethasone for use in adult patients with relapsed or refractory multiple myeloma who have previously received 1 to 3 lines of therapy.³

GMMG-HD7 is the first phase 3 trial to examine the addition of isatuximab to RVd in the induction and maintenance treatment of patients with newly diagnosed multiple myeloma who were eligible to receive high-dose therapy (HDT) and autologous stem cell transplant (ASCT). To be eligible for enrollment, patients needed to be between the ages of 18 and 70 years.

A total of 662 patients were enrolled to the trial and were randomized 1:1 to receive isatuximab plus RVd (n = 331) or RVd (n = 329). In the induction phase of treatment, patients received treatment in three 6-week cycles. Following HDT and ASCT, patients will enter the maintenance phase of the trial, where they will be randomized again to receive either isatuximab plus lenalidomide or lenalidomide alone for 4-week cycles. The study will come to completion after 3 years of treatment or when patients experienced progressive disease.

The primary end point of the trial is MRD negativity at the end of induction treatment. Secondary end points include complete response (CR) 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, according to Goldschmidt.

Baseline characteristics were found to be generally balanced between the 2 treatment arms. Across the arms, the median age was 59.5 years (range, 26-70), and the majority were male. Regarding World Health Organization performance status in the investigative arm, 47.7% had a status of 0, 41.4% had a status of 1, and 10.6% had a status of greater than 1; in the control arm, these rates were 51.1%, 39.5%, and 9.1%, respectively. Most patients across the arms did not have renal impairment at baseline, nor did they have high-risk cytogenetics.

Regarding, Revised International Staging System disease stage 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 that was not classified. In the control arm, 30.1% had stage I disease, 56.2% had stage II disease, 7.9% had stage III disease, and 5.8% had disease that was not classified.

The addition of isatuximab to RVd did not significantly impact the safety profile or dose intensity of RVd. Results showed that 63.6% of patients who received the isatuximab regimen (n = 330) experienced an any-grade adverse effect (AE) vs 61.3% of those who received RVd (n = 328). Additionally, in the investigative and control arms, 34.8% and 36.3% of patients, respectively, reported a serious toxicity with treatment. Four deaths (1.2%) were reported on the Isa-RVd arm, vs 8 (2.4%) on the RVd arm.

Furthermore, 26.4% of patients on the investigative arm experienced leukocytopenia or neutropenia vs 9.1% of those on the control arm. Four patients on the Isa-RVd arm reported infusion-related reactions; these data were not available for the RVd arm.

"Isa-RVd showed a manageable and consistent safety profile in patients with transplant-eligible, newly diagnosed multiple myeloma with no new safety signals observed,” Goldschmidt noted.

Other phase 3 trials are investigating the efficacy of isatuximab in the treatment of patients with transplant-eligible and -ineligible, newly diagnosed multiple myeloma. The drug is being explored in combination with RVd and carfilzomib, lenalidomide, and dexamethasone.

_References

_{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: the phase III GMMG-HD7 trial. Presented at: 2021 ASH Annual Meeting; December 11-14, 2021; Atlanta, GA. Abstract 463.}

_{2. FDA approves new therapy for patients with previously treated multiple myeloma. News release. FDA; March 2, 2020. Accessed December 11, 2021. https://bit.ly/2TAebOh}

_{3. FDA approves Sarclisa (isatuximab) in combination with carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma. News release. Sanofi; March 31, 2021. Accessed December 11, 2021. https://bit.ly/39za7X4}