Isatuximab Quadruplet Yields Rapid, Deep Responses in Newly Diagnosed Myeloma

The addition of isatuximab (Sarclisa) to both initial treatment with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) and maintenance therapy with Rd induced more sustainable minimal residual disease (MRD) negativity, compared with VRd and Rd maintenance alone, in patients with transplant-ineligible newly diagnosed multiple myeloma, according to updated data from the phase 3 IMROZ study (NCT03319667) presented at the 2024 ASH Annual Meeting.¹

Isatuximab/VRd elicited sustained MRD rates in newly diagnosed myeloma.

Findings indicated that significantly more patients experienced sustained MRD negativity at 10^-5 sensitivity for 12 months or longer with the addition of the CD38 antibody. In the isatuximab arm, 46.8% of patients saw their MRD negativity extend to 12 months or beyond compared with 24.3% of those who received VRd. Moreover, 25.7% of those in the isatuximab-VRd group had sustained MRD negativity for 36 months or longer compared with 7.2% of those in the VRd group.

“Isatuximab-VRd followed by isatuximab-Rd led to a rapid and greater depth of response by MRD negativity over time and demonstrated a consistent benefit over VRd across every time point up to 60 months, which ultimately translated into a progression-free survival [PFS] benefit that was maintained over time,” lead investigator Robert Z. Orlowski, MD, PhD, of the Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center, said during a presentation of the results. “These data strongly support the benefit of isatuximab in addition to VRd as initiation therapy, as well as the addition of isatuximab to Rd during maintenance in transplant-ineligible patients with newly diagnosed multiple myeloma.”

In September 2024, the FDA approved isatuximab with VRd for patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant, based on an earlier assessment of the IMROZ study that was published in the New England Journal of Medicine.^2,3 At the time of the approval, there was a 40% reduction in the risk of disease progression or death with the addition of isatuximab to VRd (HR, 0.60; 95% CI, 0.44-0.81; P = .0009). The median PFS was not yet reached (NR; 95% CI, NR-NR) in the isatuximab-VRD arm vs 54.3 months (95% CI, 45.2-NR) in the VRd arm. The approval followed a priority review.

In the phase 3 IMROZ study, investigators randomized 446 patients in a 3:2 ratio to receive initial treatment with isatuximab-VRd (n = 265) or VRd alone (n = 181) for four 6-week cycles.³ Intravenous isatuximab was administered at 10 mg/kg, subcutaneous bortezomib was administered at 1.3 mg/m², oral lenalidomide was given at 25 mg, and dexamethasone was administered either orally or intravenously at 20 mg.

The initiation phase was followed by a maintenance phase, wherein treatment was given in 4-week cycles. Those in the VRd initiation arm were permitted to crossover to the isatuximab group at the time of progressive disease. In the maintenance phase, the bortezomib was dropped. In the investigational arm, maintenance was isatuximab plus Rd in the investigative group compared with Rd alone in the control group.

The median age of patients in both arms was 72 years, with roughly one-quarter falling into the 75-to-80–year range. Most patients had an ECOG performance status of 0 or 1, with approximately 11% having a status of more than 1. High-risk cytogenetics were seen in 15.1% of those in the isatuximab arm and 18.8% of those in the control arm. High-risk chromosomal abnormalities were seen in 7.2% of those in the isatuximab arm and 8.3% of those in the control arm.

For the MRD assessment, cells were analyzed using clonoSEQ next-generation sequencing at a sensitivity of at least 10^-5 from bone marrow aspirates. This assessment was completed at baseline, 6 months, and then at months 12, 18, 24, and 36 followed by annually. Findings presented at the meeting were for both 10^-5 and for 10^-6 sensitivity.

“There was a rapid increase around 6 months, which is when the first measurement was made, at both 10^-6 and 10^-5 the rates are higher with isatuximab-VRd compared with VRd,” Orlowski said. “More patients achieved MRD negativity at later time points with isatuximab-VRd than VRd throughout the study. The increase in MRD negativity was much more dramatic with isatuximab-VRd than with VRd by comparison.”

An analysis was conducted looking at PFS in those who achieved MRD. At the 10^-5 sensitivity, those who achieved MRD at any point saw a 44% reduction in the risk of progress or death with isatuximab vs the control (HR, 0.564; 95% CI, 0.325-0.979; P = .0418). For those who achieved MRD negativity in the first 6 months, there was a 42% reduction in the risk of progression or death with the addition of the monoclonal antibody (HR, 0.582; 95% CI, 0.296-1.068; P = .0784).

Landmark analyses examined the time points of MRD achievement. Of those with assessable MRD (n = 307), 49.7% in the isatuximab group achieved MRD negativity by 10^-5 sensitivity in the first 6 months compared with 41.1% of those in the VRd group. By month 12, 54.0% of those in the isatuximab group achieved MRD compared with 39.2% of those in the control group. The rate of MRD leveled in the control arm but continued to increase in the isatuximab arm, with an MRD negativity rate of 67.6% at 48 months and 76.1% at 60 months for isatuximab compared with 41.7% and 40.0%, respectively, in the control group. These findings were similar when looking at those with a complete response who also achieved MRD negativity.

“A higher proportion of patients had MRD and CR with isatuximab-VRd vs VRd, which was maintained over time, even with late follow-up, although at 5 years it was immature,” Orlowski said.

There were some patients with MRD negativity in the initiation phase who converted to MRD positivity, Orlowski pointed out. For the full intention-to-treat population (n = 446), the MRD rate was 36.6% and 25.4% with and without isatuximab, respectively. Of these patients, 9.3% in the isatuximab arm became MRD positive by month 12, as compared with 22.2% of those in the control group. At month 18, 5.6% of those who achieved MRD negativity in the initiation phase became positive compared with 34.5% of those in the VRd group. By month 36, 57 of the original 97 patients in the isatuximab initiation group remained MRD negative compared with 23 of 46 in the VRd arm.

Sustained MRD negativity remained consistent when assessing MRD by the 10^-6 sensitivity. For this threshold, the sustained MRD negative rate was 27.9% at 12 months or more for those receiving isatuximab compared with 12.7% for those in the control group. For 36 months or more, at a sensitivity threshold of 10^-6, the MRD-negative rate was 12.1% for isatuximab compared with 3.9% for VRd.

Sustained MRD was seen across all key subgroups, especially in those deemed frail, Orlowski noted. “Although numbers are small, they nonetheless had a really nice benefit with isatuximab plus VRd,” he said. “If you look at those with high-risk cytogenetics, they also had a nice benefit.”

PFS was also superior with isatuximab plus VRd compared with VRd for those with sustained MRD negativity of 12 months or longer, although these findings were not statistically significant (HR, 0.818; 95% CI, 0.376-1.777; P = .6117). For those who sustained MRD for 24 months or longer, PFS became similar between groups (HR, 0.973; 95% CI, 0.275-3.450; P = .9665).

References

1. Orlowski RZ, Dimopoulos M-A, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) in patients with newly diagnosed multiple myeloma (NDMM): analyses of minimal residual disease (MRD) negativity dynamics in the phase 3 Imroz study. Blood. 2024;144(suppl 1):770. doi:10.1182/blood-2024-203818
2. FDA approves isatuximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. September 20, 2024. Accessed December 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-isatuximab-irfc-bortezomib-lenalidomide-and-dexamethasone-newly-diagnosed-multiple
3. Bacon T, Dimopoulos M-A, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;391(17):1597-1609. doi:10.1056/NEJMoa2400712