Isatuximab Combo Shows Activity in Elderly Transplant-Ineligible Myeloma

"Our results supports that a modified version of the IMROZ [NCT03319667] regimen is effective and tolerable for older patients in more frail condition," according to the study authors.

Combining isatuximab-irfc (Sarclisa) with bortezomib (Velcade), lenalidomide (Revlimid), and limited dexamethasone appeared to be effective and tolerable among elderly patients with multiple myeloma who are ineligible to undergo autologous hematopoietic stem cell transplantation (HSCT), according to findings from the phase 2 REST trial (NCT04939844) published in Lancet Haematology.¹

With a median follow-up of 27.0 months (IQR, 23.0-33.7), a minimal residual disease (MRD)–negative complete response (CR) occurred in 37% (n = 19/51) of evaluable patients. Additionally, data showed an objective response rate (ORR) of 100% (95% CI, 93%-100%), which included a CR or better in 47% (n = 24) and a very good partial response (VGPR) or better in 82% (n = 42).

The median progression-free survival (PFS) was not reached at the time of analysis. Treatment produced PFS rates of 86% (95% CI, 77%-96%) at 12 months and 78% (95% CI, 67%-90%) at 18 months. The overall survival (OS) rate was 90% (95% CI, 82%-99%) at 12 months and 88% (95% CI, 80%-98%) at 18 months.

“The results from the REST study complement those of the phase 3 IMROZ study [NCT03319667], in which treatment with isatuximab plus bortezomib/lenalidomide/dexamethasone in patients younger than 81 years with newly diagnosed multiple myeloma ineligible for autologous HSCT led to statistically significant improvements in MRD-negative [CR] rate and [PFS],” Frida Bugge Askeland, MD, from the Department of Hematology at the Oslo Myeloma Center of Oslo University Hospital in Oslo, Norway, wrote with study coauthors.^1,2 “Our results supports that a modified version of the IMROZ regimen is effective and tolerable for older patients in more frail condition.”

Investigators of the academic, single-arm phase 2 REST trial assigned a total of 51 patients to receive isatuximab at 10 mg/kg intravenously on days 1, 8, 15, and 22 of cycle 1 and days 1 and 15 of cycles 2 to 18; bortezomib at 1.3 mg/m² subcutaneously on days 1, 8, and 15 of cycles 1 to 8; and lenalidomide at 25 mg orally on days 1 to 21. Additionally, treatment included dexamethasone at 20 mg orally on days 1, 8, 15, and 22 for the first 2 cycles only.

The trial’s primary end point was the MRD-negative CR rate as determined via next-generation flow cytometry during or after 18 cycles of therapy. Secondary end points included ORR based on International Myeloma Working Group (IMWG) criteria, PFS, OS, safety, and health-related quality of life.

Patients 18 years and older with documented newly diagnosed multiple myeloma and measurable disease per IMWG guidelines were eligible for enrollment on the trial. Additional eligibility criteria included having ineligibly to receive high-dose melphalan (Alkeran) and autologous HSCT, an ECOG performance status of 0 to 3, and adequate hemoglobin levels.

The median age was 77 years (IQR, 74-80), and most patients were female (53%). Most of the study population had an ECOG performance status of 0 (55%), non-frail status (55%), IgG disease (59%), International Staging System (ISS) stage III disease (41%), and Revised ISS stage II disease (63%). The median eGFR measurement was 66 mL/min per 1.73 m² (IQR, 52-79), with most patients having 60 mL/min per 1.73 m² or higher (59%).

Data showed a median relative dose intensity of 97% (IQR, 92%-100%) for isatuximab, 96% (IQR, 84%-100%) for bortezomib, 83% (IQR, 60%-92%) for lenalidomide, and 100% (IQR, 100%-100%) for dexamethasone.

Grade 2 or higher adverse effects (AEs) included infections (76%), neutropenia (55%), bone pain (31%), constipation (29%), thrombocytopenia (27%), and maculopapular rash (24%). Additionally, the most common grade 3/4 toxicity included neutropenia (55%), infections (41%), and thrombocytopenia (22%).

Two patients discontinued study treatment before the nineteenth cycle due to toxicity, including 1 due to retinitis associated with cytomegalovirus potentially related to isatuximab and lenalidomide and another patient due to muscle and joint pain potentially related to lenalidomide.

References

1. Askeland FB, Haukås E, Slørdahl TS, et al. Isatuximab, bortezomib, lenalidomide, and limited dexamethasone in patients with transplant-ineligible multiple myeloma (REST): a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2025;12(2):e120-e127. doi:10.1016/S2352-3026(24)00347-8
2. Facon T, Dimopoulos M-A, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. J Clin Oncol. 2024;391(17):1597-1609. doi:10.1056/NEJMoa2400712