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

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] <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 <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.

Terpos:Amgen: Honoraria, Other: Travel expenses, Research Funding; BMS: Honoraria; AstraZeneca: Honoraria, Other: Travel expenses; EUSA Pharma: Honoraria, Other: Travel expenses; GSK: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Menarini/Stemline: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria; Antengene: Honoraria, Research Funding; Swixx: Honoraria. Kastritis:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria; Amgen: Honoraria; Genesis Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Delimpasi:GSK: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Kotsopoulou:BMS: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; GENESIS PHARMA: Honoraria; GSK: Honoraria, Research Funding; GILEAD SCIENCES: Honoraria; INTEGRIS: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Sanofi: Honoraria, Research Funding; Vianex: Honoraria; Winmedica: Honoraria. Labropoulou:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Demo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genesis Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Johnson and Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; WinMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vianex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ntanasis-Stathopoulos:AstraZeneca: Honoraria; Cellectar Biosciences: Research Funding; Janssen-Cilag: Honoraria. Fotiou:Sanofi: Honoraria; Janssen: Honoraria. Migkou:GlaxoSmithKline: Honoraria; Janssen Cilag: Honoraria. Psarros:Health Data Specialists: Current Employment. Gavriatopoulou:Amgen: Consultancy; Beigene: Research Funding; AbbVie: Honoraria; BMS: Research Funding; Cellectar Biosciences: Research Funding; GSK: Consultancy, Honoraria; Integris: Honoraria; Takeda: Consultancy, Honoraria; Swixx: Honoraria; Janssen Cilag: Honoraria; Karyopharm: Consultancy; Genesis Pharma: Honoraria. Dimopoulos:AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; Menarini: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; BeiGene Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; Amgen, Abbvie, Takeda, Beigene, BMS, GSK, Janssen, Menarini, Regeneron, Sanofi: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Swixx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.