Updates from a Phase Ib Study of Isatuximab, Bortezomib and Dexamethasone Plus Cyclophosphamide or Lenalidomide in Transplant Ineligible Newly Diagnosed Multiple Myeloma

Background: The combination of bortezomib and dexamethasone (Vd) with either cyclophosphamide (C) or lenalidomide (R) is an effective regimen in multiple myeloma (MM). Isatuximab (Isa), a CD38 monoclonal antibody, is approved in combination with pomalidomide and dexamethasone, in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult patients with RRMM who have received at least two prior therapies including lenalidomide and a PI. Isa has demonstrated potentiation when combined with bortezomib in MM.

Aims: We report updated data from a Phase Ib study of Isa plus VCd or VRd in transplant ineligible patients with newly diagnosed MM (NDMM; NCT02513186).

Methods: Isa-VCd: Isa (10 or 20 mg/kg; weekly [QW] Cycle 1 [C1], then Q2W), V (1.3 mg/m²; twice weekly C1, then QW), C (300 mg/m²; QW C1, then Days [D] 1, 8, 15 to C12), d (20 mg; twice weekly C1, then D1, 2, 8, 9, 15, 16, 22, 23 to C12). Isa-VRd: Isa (10 mg/kg), V and d as described above; R (25 mg/day; D1–14 and D22–35). Efficacy and safety were evaluated. Conventional (M-protein levels) and minimal residual disease (MRD) International Myeloma Working Group response assessments were compared. MRD negativity was assessed at 10^-5 by next-generation sequencing and flow. Mass Spectrometry (MS) negativity (no detectable serum M-protein) was assessed for 13 patients by Immuno-Capture and Liquid Chromatography coupled to High Resolution MS.

Results: As of November 18, 2019, 17 patients were treated with Isa-VCd (10 mg/kg, n=13; 20 mg/kg, n=4), 27 with Isa-VRd; 53% and 63% remained on treatment, respectively. Infusion reactions were seen in 53% of Isa-VCd and 63% of Isa-VRd patients; Grade ≥3 infections in 23% and 37%; serious adverse events in 47% and 52%. See table for efficacy. 3 MRD positive patients were MS positive with persistent detectable M-protein (>10 µg/mL). 8/10 MRD negative patients were MS positive (4 at 5-10 µg/mL; 4 at >10 µg/mL) and 2/10 were MS negative (<5 µg/mL). Stable residual M-protein was observed by MS up to 23 months post-MRD negativity. All patients tested by MS are still progression-free.

Conclusions: Isa-VCd/VRd shows encouraging efficacy and tolerability in NDMM. MS seems to be more sensitive than MRD; low levels of M-protein were detectable even in MRD negative patients.