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595 Preliminary Results from a Phase I Study of Isatuximab (ISA) in Combination with Bortezomib, Lenalidomide, Dexamethasone (VRd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Non-Eligible for Transplant

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Antibodies and Targeted Therapies
Hematology Disease Topics & Pathways:
Diseases, Myeloid Malignancies
Monday, December 3, 2018: 7:00 AM
Room 6F (San Diego Convention Center)

Enrique M. Ocio, MD1*, Paula Rodriguez Otero2*, Sara Bringhen, MD3, Stefania Oliva3*, Axel Nogai, MD4*, Michel Attal, MD, PhD5, Philippe Moreau6*, Dheepak Kanagavel7*, Thomas Fitzmaurice, PhD8*, Junlong Wu9* and Joaquin Martinez-Lopez, MD, PhD10*

1University Hospital of Salamanca (IBSAL) & Cancer Research Center (IBMCC-CSIC-USAL), Salamanca, Spain
2University Clinic of Navarra, Center for Applied Medical Research (CIMA), IDISNA, Pamplona, Spain
3Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy
4Internal Medicine III, Charité Campus Benjamin Franklin, Berlin, Germany
5Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
6University Hospital, Nantes, France
7Sanofi, Vitry-Alfortville, FRA
8Sanofi, Cambridge, MA
9Sanofi R&D, Beijing, China
10Hematology, Hospital Universitario 12 de Octubre, CNIO, Complutense, Madrid, Spain

Background: Isatuximab (ISA) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells via direct tumor targeting and immune cell engagement. ISA, combined with bortezomib, has demonstrated strong potentiation in a multiple myeloma (MM) xenograft model (Clin Cancer Res 2014:20:4754). This supported evaluation of ISA with bortezomib combinations in pts with newly diagnosed multiple myeloma (NDMM) ineligible for transplant. In the initial cohort, ISA combined with bortezomib, cyclophosphamide, and dexamethasone (dex) was well tolerated with 73% of pts achieving very good partial response (VGPR) or better and 40% with complete response (CR) (Blood 2017; 130: 3160). The combination of bortezomib, lenalidomide, and dex (VRd) is also effective in NDMM (Lancet 2017:389:519–27). Here, we report initial data from a Phase Ib study of ISA plus VRd in pts with NDMM (NCT02513186).

Methods: Pts with NDMM ineligible for transplantation were treated in 2 phases: induction and maintenance. Induction phase (four 6-week cycles [C]): ISA (10 mg/kg) on Day (D) 1, 8, 15, 22, 29 (C1), followed by D1, 15, 29 (C2–4); bortezomib (1.3 mg/m2) on D1, 4, 8, 11, 22, 25, 29, 32 (C1–4); lenalidomide (25 mg/day): D1–14 and D22–35 (C1–4); dex (20 mg/day): D1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, 33. Maintenance phase (4-week cycles): ISA (10 mg/kg) on D1, 15 (all cycles); lenalidomide (25 mg/day): D1–21 (all cycles); dex (40 mg): D1, 8, 15, 22 (all cycles), unless the pt was >75 years of age, then the dose was 20 mg. The primary objective was to evaluate safety and preliminary efficacy (overall response rate [ORR] and CR rate, [IMWG criteria]) of ISA plus VRd. Minimal residual disease (MRD) was evaluated using next generation sequencing (NGS) and flow cytometry (NGF) at a sensitivity of 10-6 in pts achieving VGPR or above. Here, we report results from a protocol-planned interim analysis.

Results: All 22 pts were included in the safety analysis (pts who received ≥1 dose of ISA) and 14 were eligible for preliminary efficacy analyses (first 14 pts who completed the 4 induction cycles). Median age was 71 (range 63–77) years. At study entry, 6, 12, and 1 pt were International Staging System Stage I, II, and III, respectively. One pt had extramedullary plasmacytoma at baseline. At data cut-off (Mar 22, 2018), the median number of cycles was 5.5 (1–9). Three pts discontinued treatment (2 VGPR, 1 not efficacy-evaluable): 2 pts due to adverse event (AE); Grade (Gr) 3 infusion reaction (IR) (ISA-related; Gr 3 dyspnea, Gr 2 glottic edema, Gr 2 nasal edema, and Gr 2 generalized rash), and Gr 5 bacteremia (lenalidomide- and dex-related); and 1 pt withdrew consent; 19 (86%) pts are continuing treatment. Dose reduction of bortezomib, lenalidomide, and dex was required in 6 (29%), 4 (16%), and 5 (28%) pts, respectively. TEAEs occurred in 19 (86%) pts. Most frequent TEAEs (any Gr; excluding laboratory abnormalities) were constipation (10 pts [46%]), IRs and peripheral edema (9 pts [41%] each), asthenia, diarrhea, and peripheral sensory neuropathy (8 pts [36%] each), hypotension (7 pts [32%]), fatigue and respiratory tract infection (6 pts [27%] each), cough and dyspnea (5 pts [23%] each). Gr ≥3 AEs were reported in 10 (46%) and serious AEs (SAEs) in 4 (18%) pts. Treatment-related SAEs occurred in 2 (9%) pts (IR and pancreatitis). IRs were Gr 1/2 in all but 1 (5%) pt (Gr 3). Gr 3/4 laboratory hematologic abnormalities: lymphopenia (8/22), neutropenia (4/22), thrombocytopenia (4/22). Of 14 efficacy-evaluable pts, ORR was 93%, with 1 stringent CR (sCR), 1 CR, 10 VGPR, 1 partial response (PR) and 1 pt with stable disease. Most importantly, 9/10 pts achieving a VGPR had IgG kappa disease. At the end of 4 induction cycles, 7 of these 9 pts had a residual M-component below 0.2 and 2 pts with only positive immunofixation, without being able to rule out the possibility of achieving CR at this time. Median time to first response was 1.4 months (end of C1) and, with a median follow-up of 7.49 months (at cut-off date), no pt has progressed, with all except 3 pts continuing on therapy. Five (38.5%) of 13 pts achieved MRD-negative status (by NGF and NGS, or NGS only).

Conclusion: These data suggest that ISA plus VRd followed by ISA plus Rd is well tolerated with a high ORR of 93%. All responders had VGPR or CR except 1 pt with PR. Quality of CR may have been underestimated due to ISA interference which could be resolved with an interference assay.

Funding: Sanofi

Disclosures: Ocio: Janssen: Consultancy, Honoraria; AbbVie: Consultancy; BMS: Consultancy; Pharmamar: Consultancy; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Rodriguez Otero: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Janssen: Consultancy, Honoraria; Clínica Universidad de Navarra: Employment; Bristol Myers Squibb: Research Funding. Bringhen: Amgen: Honoraria, Other: Advisory Board; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy. Oliva: Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Attal: Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janseen: Consultancy, Research Funding; Sanofi: Consultancy. Moreau: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kanagavel: Sanofi: Employment, Equity Ownership. Fitzmaurice: Sanofi: Employment, Equity Ownership. Wu: Sanofi: Employment, Equity Ownership. Martinez-Lopez: Janssen: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau.

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