Isatuximab/VRd in Transplant-Ineligible, Newly Diagnosed MM Approved in Japan

Isatuximab plus bortezomib, lenalidomide, and dexamethasone demonstrated enhanced MRD-negativity rates and a PFS benefit in patients with newly diagnosed multiple myeloma.

Isatuximab-irfc (Sarclisa) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone has been approved for the treatment of patients with autologous stem cell transplant-ineligible, newly diagnosed multiple myeloma by the Ministry of Health, Labour, and Welfare in Japan, according to a press release from the developer, Sanofi.¹

Previously, the isatuximab combination was approved in autologous stem cell transplant-ineligible newly diagnosed multiple myeloma by the FDA and China’s National Medical Products Administration (NMPA).^2,3 In January 2025, isatuximab with pomalidomide (Pomalyst) and dexamethasone was approved for patients with pretreated multiple myeloma by China’s NMPA.⁴

Supporting data for this approval comes from the phase 3 IMROZ trial (NCT03319667) evaluating isatuximab plus bortezomib, lenalidomide, and dexamethasone compared with the triplet of bortezomib, lenalidomide, and dexamethasone treatment of adult patients with newly diagnosed, transplant-ineligible multiple myeloma.⁵

“In recent years, new multiple myeloma cases have increased steadily in Japan and other Asian-Pacific nations, creating a need for new treatment approaches, particularly in the front-line setting,” Olivier Nataf, global head of Oncology at Sanofi, stated in the press release.¹ “While isatuximab-based combinations have been approved for relapsed/refractory patients in Japan, this approval represents the first indication for certain patients who are newly diagnosed. We are pleased to offer physicians an important new option for their patients earlier in the treatment journey, building upon our continued commitment to advancing innovative oncology treatments in difficult-to-treat hematologic malignancies around the world.”

In the intention-to-treat population, at a median follow-up of 59.7 months, 58.1% of patients achieved sustained minimal residual disease (MRD) negativity at 10^-5 sensitivity in with the trial combination vs 43.6% of patients in the control arm (OR, 1.79; 95% CI, 1.22-2.63; P = .0014). MRD negativity was sustained for 12 months or longer in 46.8% of the combination arm and 24.3% of the control arm (OR, 2.73; 95% CI, 1.80-4.14; P <.0001).

Via landmark analyses during the trial’s initiation and maintenance phases, MRD negativity rates were 49.7% in the combination arm vs 41.1% in the control arm at 6 months; 54.0% vs 39.2%, respectively, at 12 months; 64.1% vs 41.0% at 24 months; 68.0% vs 50.8% at 36 months; 67.6% vs 41.7% at 48 months; and 76.1% and 40.0% at 60 months.

Additionally, fewer patients in the combination arm who achieved MRD negativity in the initiation phase transitioned to MRD positivity during the maintenance phase when compared with those in the control arm. There was also an observed increased time to progression benefit for those in the combination arm who converted to MRD positivity after MRD negativity (HR, 0.236; 95% CI, 0.089-0.624; P = .0036).

Of patients who achieved MRD negativity at 6 months of trial start, a progression-free survival (PFS) benefit was observed for those who received isatuximab vs those who didn’t (HR, 0.562; 95% CI, 0.296-1.068; P = .0784). Those who demonstrated a complete response and MRD negativity in the combination arm had better PFS (HR, 0.539; 95% CI, 0.304-0.953; P = .0336).

Patients were randomly assigned, in a 3:2 ratio, to either receive or not receive intravenous isatuximab at 10 mg/kg on days 1, 8, 15, 22, and 29 of cycle 1 and days 1, 15, and 29 for cycles 2 to 4, and all patients received 1.3 mg/m² of subcutaneous bortezomib, 25 mg of oral lenalidomide, and 20 mg of intravenous or oral dexamethasone during the initiation phase. During the maintenance phase, patients received 10 mg/kg of intravenous isatuximab on days 1 and 15 for cycles 5 to 17, and then only on day 1 every cycle thereafter, and then 25 mg of oral lenalidomide on days 1-21 and 20 mg of intravenous or oral dexamethasone on days 1, 8, 15, and 22.

Eligible patients had newly diagnosed multiple myeloma who were unable for transplant and had evidence of measurable disease and written informed consent.⁶

Patients younger than 18 years who received prior treatment for multiple myeloma and had an ECOG performance status greater than 2, hypersensitivity to the study medications, inadequate organ function, and prior or ongoing disease/health conditions incompatible with study objectives were not permitted participation.

“These data support the benefit of isatuximab in addition to [bortezomib, lenalidomide, and dexamethasone] as initiation therapy, as well as the addition of isatuximab to [lenalidomide and dexamethasone] during maintenance in transplant-ineligible patients with newly diagnosed multiple myeloma,” lead study author Robert Z. Orlowski, MD, PhD, of the Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center, wrote in the presentation.⁵

References

1. Sarclisa approved in Japan for patients with newly diagnosed multiple myeloma. News release. Sanofi. February 25, 2025. Accessed February 25, 2025. https://tinyurl.com/4tjxmb77
2. FDA approves isatuximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. News release. September 20, 2024. Accessed February 25, 2025. https://shorturl.at/B8d3c
3. Sarclisa is the first anti-CD38 treatment in combination with standard-of-care VRd approved in China for patients with newly diagnosed multiple myeloma ineligible for transplant. News release. Sanofi. January 31, 2025. Accessed February 25, 2025. https://tinyurl.com/34nv8efm
4. Sarclisa obtains first approval in China for the treatment of adult patients with relapsed or refractory multiple myeloma. News release. Sanofi. January 13, 2025. Accessed February 25, 2025. https://tinyurl.com/5xnffr9x
5. 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
6. A study to investigate the clinical benefit of isatuximab in combination with bortezomib, lenalidomide and dexamethasone in adults with newly diagnosed multiple myeloma not eligible for transplant (IMROZ). ClinicalTrials.gov. Updated November 27, 2024. Accessed February 25, 2025. https://tinyurl.com/2mfvk9e6