Background: Isatuximab (ISA) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement. It has demonstrated strong potentiation when combined with bortezomib in a multiple myeloma (MM) xenograft model (Deckert J et al, Clin Cancer Res 2014:20:4754). The combination of bortezomib, cyclophosphamide, and dexamethasone (dex) (VCD) is an effective regimen, commonly used in newly diagnosed MM (NDMM) (Leiba M et al, Br J Haematol 2014:166:702). Here, we report initial data from a Phase Ib study of ISA plus VCD (VCDI) in patients (pts) with NDMM (NCT02513186). Methods: This dose-escalation (DE) and expansion study enrolled pts with NDMM ineligible for transplantation. Treatment consisted of 2 phases: induction and maintenance. Induction (one 6-week cycle [cycle (C)1] followed by eleven 4-week cycles [C2-12]): ISA (10 or 20 mg/kg, sequentially enrolled) weekly during C1, then every 2 weeks; subcutaneous bortezomib (1.3 mg/m2) on Days (D)1, 4, 8, 11, 22, 25, 29, and 32 (C1), then weekly (C2-12); cyclophosphamide (300 mg/m2) weekly (C1) then on D1, 8, and 15 (C2-C12); dex (20 mg) on D1, 4, 8, 11, 15, 22, 25, 29, and 32 (C1) then D1, 2, 8, 9, 15, 16, 22, and 23 (aged Results: Enrolment is now complete; 17 pts were treated with VCDI. During the DE phase, 4 pts were treated at 10 mg/kg and 4 pts at 20 mg/kg. Based on initial safety (no DLTs occurred at either dose; MTD was not reached) and pharmacokinetic (PK) data, ISA 10 mg/kg was chosen as the recommended dose for the expansion cohort and 9 additional pts were treated at this dose (total 13 pts at 10 mg/kg). Median age was 71 (68-80) years. At baseline, 1, 1, and 15 pts were ISS Stage I, II, and III, respectively. At data cut-off (Dec 31, 2016), pts across both doses had been treated for a median of 3.0 (0.5-14.0) months (mo). Two pts discontinued treatment due to an adverse event (AE) (10 mg/kg: Grade [Gr] 3 bronchospasm and Gr 3 infusion-associated reaction [IAR]; 20 mg/kg: sudden death [during C1, not treatment related]) and 1 pt (10 mg/kg) discontinued due to disease progression. ISA dose omission was required in 5/13 (38%) pts at 10 mg/kg (Gr 2 bronchitis, Gr 2 mesenteric vein thrombosis, Gr 3 respiratory tract infection, Gr 3 hypertension, Gr 3/4 neutropenia) and none at 20 mg/kg. Dose omission of bortezomib, cyclophosphamide, and dex was required in 7, 5, and 8 pts, respectively. All pts experienced ≥1 AE. Most frequent AEs across both doses (any Gr; excluding laboratory abnormalities): IARs, 8 pts (47%); back pain, 7 pts (41%); nausea, 5 pts (29%); bronchitis, 5 pts (29%); peripheral neuropathy, hypertension, diarrhea, constipation, peripheral edema, and rash, 4 pts each (24%). Gr ≥3 AEs were reported in 11 (65%) pts and serious AEs (SAEs) in 4 (24%) pts (Gr 3 bronchospasm, Gr 2 mesenteric vein thrombosis, Gr 3 dorsal pain, Gr 5 sudden death). Except Gr 3 bronchospasm, no SAEs were treatment related. Nine IARs occurred in 8 pts, all in the first infusion. IARs were Gr 1/2 in all but 1 pt (Gr 3 bronchospasm). Gr 3/4 hematologic abnormalities (laboratory assessment): lymphopenia (8/16 evaluable pts), leukopenia (3/16), neutropenia (3/16), thrombocytopenia (1/16), anemia (1/16). From 15 efficacy-evaluable pts the ORR was 87% (13/15), including 2 stringent CRs, 3 CRs, 4 very good partial responses (VGPRs), and 4 partial responses. Two pts achieved a best response of stable disease, lasting 5 and 12 cycles, respectively. Median time to first response was 1.5 mo. Median duration of response in the DE phase was 11.1 mo, and 14 (82.4%) pts are continuing on treatment. ISA PK appeared unaffected by co-administration with VCD. Conclusions: These data suggest that VCDI is generally well tolerated with many pts demonstrating at least VGPR. Safety and efficacy data (including minimal residual disease status) with longer-term follow-up will be presented at the meeting. Funding: Sanofi Disclosures Ocio: Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Array Pharmaceuticals: Research Funding; Mundipharma: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Research Funding; BMS: Honoraria; Janssen: Honoraria. Bringhen: JJ: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria; BMS: Honoraria. Oliva: Celgene: Honoraria; Takeda: Honoraria. Rodriguez-Otero: BMS: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Kanagavel: Sanofi: Employment. Oprea: Sanofi RD Sanofi: Other: Stock holder. Wei: Sanofi RD Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Janssen: Honoraria.