Isatuximab with bortezomib, cyclophosphamide, and dexamethasone followed by isatuximab and lenalidomide maintenance in newly diagnosed multiple myeloma patients with severe renal impairment: Final analysis of a phase 2 study by the greek myeloma study group Free

Severerenal impairment (RI) is a common complication of multiple myeloma (MM), limiting therapeutic options and negatively impacting outcomes. There is a need for effective, kidney-safe induction regimens to improve renal and hematologic responses. Isatuximab (Isa), an anti-CD38 monoclonal antibody, has shown efficacy and improved renal recovery in combination with pomalidomide/dexamethasone in relapsed/refractory (RR) MM. Data on the safety and efficacy of frontline regimens designed for this subgroup remain limited. We evaluated the renal/hematologic efficacy and safety of Isa with bortezomib, cyclophosphamide and dexamethasone (IsaVCd), followed by Isa and lenalidomide (R) maintenance in newly diagnosed (ND) MM patients (pts) with severe RI.

EAE116 (NCT05147493) is an investigator-initiated, phase 2, prospective, open-label, multicenter study of previously untreated NDMM pts with severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73m² or requiring dialysis). Pts received six 28-day cycles of IsaVCd as induction treatment (Isa 10 mg/kg IV [C1: QW ; C2–6: Q2W]; bortezomib 1.3 mg/m² SC [C1: D1, 4, 8, 11; C2–6: QW]; cyclophosphamide 300 mg/m² IV [C1: D1, 8, 15; C2–6: QW]; dexamethasone 40 mg [or 20 mg for pts ≥75 years old] PO/IV [C1: D1, 2, 3, 4, 9, 10, 11, 12; C2–6:QW]). In the maintenance phase (C7 onwards), pts received Isa 10 mg/kg IV Q4W and daily R 10 mg PO (or per renal function) until disease progression (PD), death, unacceptable toxicity or study end. Endpoints included renal response rate (RRR), ORR (≥PR), PFS, OS, time to response and safety.

As of 15 April 2025, 51 pts (median eGFR at screening: 18.5 mL/min/1.73m² [range 4.0–29.0]) had been enrolled across 5 Greek centers and received ≥1 dose of IsaVCd; 32 (62.7%) were still on treatment and 19 (37.3%) discontinued (death: 11 [21.5%]; PD: 4 [7.8%]; consent withdrawal: 2 [3.9%]; physician decision: 2 [3.9%]). At baseline, median age was 70.0 years (range 46.0–89.0; 76.5% ≥65 years); 32/51 pts (62.7%) were male; 45/51 (88.2%) had ECOG PS ≤1; median involved FLC (iFLC) was 1791 mg/L (range: 7.9 -52,900); 47 (92.2%) had ISS stage III and 24 pts (47.1%) had R-ISS stage III disease. Moreover, 7 (13.7%) pts had high-risk cytogenetics , and 6 (11.8%) had soft tissue plasmacytomas.

At a median follow-up of 19.7 months (range 0.1–32.0), all pts received a median of 16.0 treatment cycles (range 1.0–33.0) and 40 (78.4%) had completed 6 months of treatment. During the induction phase, median Isa dose exposure was 22.8 mg/kg/28-day; median Isa dose administered was 100.0% (range 25.0–100.0%) of the planned dose and dose skips occurred in 17/51 (33.3%) pts; 9 (17.6%) due to AEs. In the maintenance phase, median Isa exposure was 9.6 mg/kg/28-day (range 7.3- 11.3); median Isa dose administered was 100.0% (range 80.0-100.0%) of the planned dose and dose skips occurred in 2/40 (5.0%) pts due to AEs. Among renal-response-evaluable pts (N=50), 36 (72.0%) achieved ≥ minor renal response (MRR) in a median time of 1.1 months (range 0.9–26.4). RRR (≥ renal PR) was observed in 18 pts (36.0%; complete RR: 15 pts [30.0%]; partial RR: 3 pts [6.0%]), with a median time to first response of 2.3 months (range 0.9–15.1). Among 11 pts (21.6%) dialysis-dependent at baseline, 6 (54.5%) became dialysis independent.

Hematologic ORR was 84.3% (sCR: 11 pts [21.6%], CR: 7 pts [13.7%], VGPR: 19 pts [37.3%], PR: 6 pts [11.8%]), with a median time to first response of 1 month (range 0.9–11.5). Progression-free survival (PFS) was 77.6% at 12 months (95% confidence interval [CI]: 63.2–86.9) and 60.3% at 24 months (95% CI: 42.7–74.0). Overall median PFS and time to progression were not reached, with 17 PFS events: 4 PD and 13 deaths. OS was 82.96 % at 12 months (95 % CI: 70.44-91.64) and 63.58 % at 24 months (95 % CI: 46.00-77.17). TEAEs occurred in 86.3% (44/51) pts overall; Grade ≥3 TEAEs in 39.2% (20/51), Grade 5 events in 21.6% (11/51), ≥1 serious TEAEs in 35.3% (18/51).

Data from the final analysis demonstrate that IsaVCd induction treatment followed by IsaR maintenance elicits notable renal and hematologic responses in NDMM pts with severe RI and advanced risk features. Responses were rapid, including high rates of dialysis independence, with a favorable safety profile consistent with known toxicities of the individual agents. These findings support IsaVCd as a promising frontline option for patients with MM and severe RI.