Replacing Steroids in Transplant-Ineligible Multiple Myeloma: The Phase 2 Isatuximab-Bortezomib-Lenalidomide-Dexamethasone Rest Study

Background: Adding CD38-targeting immunotherapy to bortezomib-lenalidomide-dexamethasone (VRd) or lenalidomide-dexamethasone (Rd) deepens responses and prolongs progression free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem-cell transplantation (ASCT) [1, 2]. In the MAIA trial, treatment with daratumumab-Rd resulted in measurable residual disease negative (MRD 10-5) complete response (CR) rates of 24.2% (Rd: 7.3%), in a study population with a median age of 73 years. In the phase 3 Intergroupe Francophone du Myélome (IFM), BENEFIT trial of isatuximab (Isa), lenalidomide and time-limited dexamethasone with or without weekly bortezomib, for patients with NDMM ineligible for ASCT, the quadruplet combination achieved higher rates of MRD negativity (10-5) at 18 months than the triplet (53% vs 26%, OR 3.16), but no difference is observed for survival data. However, in the BENEFIT trial, patients ≥ 80 years of age were excluded and dexamethasone was not stopped before cycle 13 [3]. Corticosteroids have acute side effects such as cognitive, behavioral and mood changes as well as insomnia, weakness and fatigue. Long-term use increases the risk of infections, hyperglycemia, myopathy and secondary osteoporosis. Infections are one of the main causes of complications and death during active first line treatment and this rises with age. We present the primary endpoint (MRD-negative (10-5) CR) and 12- and 18-month PFS with a regimen of isatuximab-bortezomib-lenalidomide with minimal use of corticosteroids, in NDMM patients who were ineligible for ASCT. Aim: To evaluate isatuximab in combination with bortezomib and lenalidomide with minimal dexamethasone as first-line treatment in transplant-ineligible myeloma patients. Methods: REST is an academic, single arm, open-label, phase 2 study of NDMM patients ineligible for ASCT. 51 patients were included and received Isa-VR(d) (Isa: 10 mg/kg IV Days 1, 8, 15, 22 during cycle 1, Q2W cycle 2-18; V: 1.3 mg/m2 SC Days 1, 8, 15 during cycle 1-8; R: 25 mg PO Days 1-21 during all cycles; d: 20 mg PO Days 1, 8, 15, 22 only for the first 2 cycles), all 28-day cycles. The primary endpoint was the proportion of patients who achieved MRD negative (Euroflow NGF 10-5) CR during/or after 18 cycles of study treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), safety evaluations and patient-reported outcome. Results: Recruitment was completed in January 2023. The median age was 77 years (70-88), 33 patients (64.7%) were >75 years and 16 (31.3%) were >80 years. 27 patients (53%) were female and 23 (45.1%) had an ECOG performance status of >1. Nine patients (17.6%) had high-risk cytogenetics, 29 (56.8%) had impaired renal function (eGFR < 60 ml/min) and eight (15.6%) had an eGFR<45. MRD negative CR (10-5) was achieved in 19 patients (37.3%). The ORR was 100% (51/51), including 24 (47.1%) >CR, 42 (82.4%) >very good partial response and nine (17.6%) partial response. At a median follow up of 26 months the median PFS was not reached. The 12-month PFS was 85.7% (77 - 96) and the 18 months PFS was 76.8 (66 - 90). The 12-month OS was 90.0% (82 - 99) and the 18 months OS was 87.9% (79 - 98). At 26 months of median follow up disease progression or death had occurred in 17 patients (33.3%) and six (11.8%) had died. Only one (5.3%) patient with a CR MRD-negative response had progressed. During combination treatment a total of 47 serious adverse events grade 3 or higher were reported in 27 (53%) of the patients. The most common adverse events of grade >3 were neutropenia (in 54.9%) and infections (in 41.2%). Conclusions: Isa-VR(d) in the transplant-ineligible population with a high median age of 77 years has a tolerable safety profile. MRD negative CR was achieved in 37.3%, 12 months PFS was 85.7%, and 18 months PFS was 76.8%. Acknowledgements: Sanofi funded this research. Facon, T., et al., Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. New England Journal of Medicine, 2024. Facon, T., et al., Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med, 2019. 380(22): p. 2104-2115. Leleu, X., et al., Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nature Medicine, 2024: p. 1-7.