A Phase 2 Study of 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
Authors: Terpos Evangelos , Kastritis Efstathios , Symeonidis Argiris , Pouli Anastasia , Delimpasi Sosana , Katodritou Eirini , Hatzimichael Eleftheria , Ntanasis-Stathopoulos Ioannis , Malandrakis Panagiotis , Fotiou Despina , Migkou Magdalini , Theodorakakou Foteini , Spiliopoulou Vasiliki , Syrigou Rodanthi , Eleutherakis-Papaiakovou Evangelos , Manousou Kyriaki , Gavriatopoulou Maria , Dimopoulos Meletios A. 
Published: December 2023

Introduction
Renal impairment (RI), a common complication of multiple myeloma (MM), is associated with increased risk of early death. Reversal of MM-associated RI is a key predictor of improved survival. Regimens containing bortezomib and dexamethasone are the treatment backbone for newly diagnosed (ND) patients (pts) with MM and severe RI, even those requiring dialysis. In the ICARIA-MM study, the addition of isatuximab (Isa) to pomalidomide and dexamethasone improved the renal response rate (RRR) in pts with relapsed/refractory MM and RI. We investigated the effect of induction treatment with Isa plus bortezomib, cyclophosphamide, and dexamethasone (VCd) on the renal function of pts with NDMM and severe RI. Additionally, we evaluate the efficacy and safety of IsaVCd induction, followed by Isa and lenalidomide (Len) maintenance.
Methods
EAE116 (NCT05147493) is an ongoing, investigator-initiated, phase II, prospective, open-label study aiming to enroll ~51 pts in six Greek hospitals. Eligible pts are adults with documented NDMM by International Myeloma Working Group (IMWG) criteria and severe RI (estimated glomerular filtration rate [eGFR] &lt;30 ml/min/1.73m 2) or in need of dialysis. Pts must also have adequate bone marrow and hepatic function and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Excluded are pts with prior/current systemic therapy or stem cell transplantation for any plasma cell dyscrasia, history of malignancy other than MM, meningeal involvement of MM, cardiac disease, hepatitis, ongoing grade (gr) ≥2 peripheral neuropathy, or those with major surgery within two weeks before cycle (Cyc)1, day (D)1.
In induction (six 28-day cycles), pts receive: Isa 10 mg/kg IV (Cyc 1: D1, 8, 15, 22; Cyc 2-6: D1, 15); bortezomib 1.3 mg/m 2 SC (Cyc 1: D1, 4, 8, 11; Cyc 2-6: D1, 8, 15, 22); cyclophosphamide 300 mg/m 2 IV (Cyc 1: D1, 8, 15; Cyc 2-6: D1, 8, 15, 22); and dexamethasone 40 mg PO or IV (Cyc 1: D1, 2, 3, 4, 9, 10, 11, 12; Cyc 2-6: D1, 8, 15, 22). In maintenance (Cyc 7 onwards), pts receive Isa 10 mg/kg IV (D1 of each Cyc) and Len 10 mg PO (or adjusted according to renal function) daily (D1-28 of each Cyc). Fifteen to 60 minutes before Isa infusions, pts receive pre-medications to mitigate potential infusion-related reactions. Treatment continues until disease progression, unacceptable toxicity, or consent withdrawal.
The study primarily assesses the RRR (proportion of pts with partial renal response or better, using the eGFR cutoff values of the IMWG response criteria) at six months of treatment with IsaVCd. Other study objectives assess the pts' overall response rate (ORR; defined as partial response [PR] or better) and the safety of IsaVCd. Adverse events are classified using the Medical Dictionary for Regulatory Activities. Herein, we present safety and efficacy data for all treated patients (cut-off date 15/05/23.
Results
Twenty-five pts have been enrolled and have received ≥1 study treatment dose; of these, 20 (80.0%) are continuing with treatment and five (20.0%) have died. At baseline, pts had a median age of 70.0 years (range 46.0-87.0), 18 (72.0%) were male, and 22 (88.0%) had ECOG PS ≤1. Thirteen (52.0%) pts were at stage II and 12 (48.0%) pts at stage III by the revised International Staging System, 6 (24.0%) pts had lytic bone lesions, 5 (20.0%) pts had high-risk cytogenetics, and 5 (20.0%) pts had soft-tissue plasmacytomas. Seven (28.0%) pts were in need of dialysis (Table 1).
At a median follow-up of 3.9 months (range 0.1-8.3), pts have received a median of 4.0 treatment cycles (range 1.0-9.0). Eight (32.0%) pts have completed ≥ 6 treatment cycles. RRR was achieved by 5/11 (45.5%) pts who had initiated treatment 6 months before the cutoff date. The median time to RR was 2.8 months (range 0.9-7.0). Of the 19 (76.0%) response evaluable pts, 11 (57.9%) achieved ORR (very good partial response: 6 [31.6%]; PR: 5 [26.3%]). The median time to first response was 1.0 months (range 0.9-1.9). Twenty (80.0%) pts had ≥1 treatment-emergent adverse events (TEAE). Of these, 10 (50.0%) pts had ≥1 gr ≥3 TEAE and 7 (43.8%) pts had ≥1 gr ≥3 serious TEAE. The most common gr ≥3 TEAE was peripheral neuropathy in 5 pts (20.0%) (Table 2).
Conclusions
Pts with NDMM and severe RI treated with upfront IsaVCd achieve RR consistent with those reported in the literature for pts receiving bortezomib-based therapy, although longer follow-up is needed to assess the regimen's impact on RI. No new safety signals were observed with IsaVCd.