Isatuximab in Combination with Bortezomib, Cyclophosphamide, and Dexamethasone, Followed By Isatuximab and Lenalidomide Maintenance in Newly Diagnosed Patients with Multiple Myeloma and Severe Renal Impairment: A Phase 2 Study of the Greek Myeloma Study Group
Authors: Terpos Evangelos , Kastritis Efstathios , Delimpasi Sosana , Kotsopoulou Maria , Papathanasiou Konstantina , Labropoulou Vasiliki , Katodrytou Eirini , Ntanasis-Stathopoulos Ioannis , Malandrakis Panagiotis , Fotiou Despina , Migkou Magdalini , Theodorakakou Foteini , Spiliopoulou Vasiliki , Kanellias Nikolaos , Eleutherakis-Papaiakovou Evangelos , Psarros Giorgos , Gavriatopoulou Maria , Dimopoulos Meletios 
Published: December 2024

Introduction
Renal impairment (RI) is a frequent complication of multiple myeloma (MM) associated with poor prognosis. Reversing MM-related RI is crucial for improving survival. Bortezomib/dexamethasone (Vd)-based regimens are essential for newly diagnosed MM (NDMM) patients (pts) with severe RI, including those requiring dialysis. Phase 3 studies (ICARIA-MM and IKEMA) showed adding Isatuximab (Isa) to standard treatment regimens improves and sustains renal responses in relapsed/refractory MM (RRMM) pts with moderate RI. In NDMM, a phase 1b study indicated Isa with Vd and cyclophosphamide (Isa-VCd) has substantial anti-myeloma effects even in pts with RI. Here, we report preliminary results from the EAE116 study, which investigates the effect of Isa-VCd as induction treatment on the renal function of NDMM pts with severe RI and its anti-myeloma effects when followed by maintenance with Isa plus lenalidomide (Len).
Methods
EAE116 (NCT05147493) is an investigator-initiated, phase 2, prospective, open-label, multicenter study currently underway in Greece, aiming to enroll 51 adult NDMM pts with severe RI, defined as estimated glomerular filtration rate [eGFR] &lt;30 ml/min/1.73m2 or requiring dialysis. Patients must also have sufficient bone marrow and liver function and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or less. Pts with prior/current systemic therapy or stem cell transplantation for any plasma cell dyscrasia are excluded. Pts receive six 28-day cycles of Isa-VCd as induction treatment (Isa 10 mg/kg IV [Cycle 1: D1, 8, 15, 22; Cycles 2-6: D1, 15]; bortezomib 1.3 mg/m2 SC [Cycle 1: D1, 4, 8, 11; Cycles 2-6: D1, 8, 15, 22]; cyclophosphamide 300 mg/m2 IV [Cycle 1: D1, 8, 15; Cycles 2-6: D1, 8, 15, 22]; and dexamethasone 40 mg (or 20 mg for pts ≥75 years of age) PO or IV [Cycle 1: D1, 2, 3, 4, 9, 10, 11, 12; Cycles 2-6: D1, 8, 15, 22]) and thereafter (Cycle 7 onwards) IsaLen as maintenance treatment (Isa 10 mg/kg IV [D1 of each cycle]; Len 10 mg PO [or according to renal function] daily [D1-28 of each cycle]) until disease progression, death, or unacceptable toxicity. The primary endpoint is the renal response rate (RRR) after six months of treatment with Isa-VCd as per the International Myeloma Working Group (IMWG) criteria.
Results
As of 31 May 2024 (data cut-off), 50 pts had received ≥1 dose of Isa-VCd and thus are included in this analysis, of which 37 (74.0%) were still on treatment and 13 (26.0%) had discontinued due to death (7 pts [14.0%]), progressive disease (2 pts [4.0%]), consent withdrawal (2 pts [4.0%]) or physician's decision (2 pts [4.0%]). Median age at baseline was 70.0 years (range 46.0-89.0), with 31 (62.0%) pts being male and 44 (88.0%) having ECOG PS ≤1. Twenty-six (52.0%) pts had stage II and 24 (48.0%) stage III disease as per the revised International Staging System (R-IIS), 7 (14.0%) had high-risk cytogenetics, 14 (28.0%) had lytic bone lesions and 6 (12.0%) had soft-tissue plasmacytomas. Additionally, 11 (22.0%) pts required dialysis. At a median follow-up of 8.5 months (range &lt;0.1-21.2), pts had received a median of 8.0 cycles (range 1.0-23.0). The overall renal response rate (minor response or better) among evaluable pts (44 pts) was 68.2%, with 14 (31.8%) pts achieving PR or better (RRR) and median time to first renal response of 1.2 months (range 0.9-6.1). Among those evaluable for myeloma response (47 pts), the ORR was 83.0% with 57.4% achieving ≥very good partial response (VGPR). The median time to first myeloma response was 1.0 month (range 0.9-11.1). Thirty-seven (74.0%) pts experienced ≥1 treatment-emergent AE (TEAE) and 15 (30.0%) pts ≥1 serious TEAE. Grade ≥3 TEAEs were reported in 18 (36.0%) pts. Most common (≥5%) Gr≥3 TEAEs were pneumonia (8%) and urinary tract infection (6%). Fatal SAEs were observed in 7 pts (14%) and corresponded to respiratory tract infection (2 pts), septic shock (2 pts), pneumonia (1 pt), respiratory failure (1 pt) and aortic aneurysm rupture (1 pt).
Conclusion
Induction treatment with Isa-VCd elicits promising myeloma responses in NDMM pts with severe RI. The safety profile is consistent with that of the individual drugs. Infections were the most common Gr≥3 TEAE, which is an expected safety finding in this frail population. We conclude that Isa-VCd may be a new option for NDMM with severe RI.