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3253 Isatuximab in Combination with Lenalidomide and Dexamethasone in Patients with High-Risk Smoldering Multiple Myeloma: Updated Safety Run-in Results from the Randomized Phase 3 Ithaca Study

Program: Oral and Poster Abstracts
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Clinical Research, Combination therapy, drug development, Diseases, Therapies, Adverse Events, Monoclonal Antibody Therapy
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Maria-Victoria Mateos, MD1, Paula Rodriguez Otero, MD, PhD2*, Youngil Koh, MD, PhD3, Joaquin Martinez-Lopez, MD, PhD4*, Gurdeep Parmar, MD5*, H. Miles Prince, MD, FRACP, FRCPA6, Hang Quach7, Paz Ribas, MD8*, Emil Hermansen, MD, PhD9*, Vania T. M. Hungria, MD, PhD10, Sevgi Kalayoglu Besisik, MD11*, Jin Seok Kim, MD, PhD12*, Xavier Leleu, MD, PhD13, Valdas Pečeliūnas, MD, PhD14*, Fredrik Schjesvold, MD, PhD15, Omur G. Sevindik, MD16*, Tatiana Lavrova, MD17*, Franck Dubin, PharmD18*, Christine Devisme, MSc19*, Lucie Lepine, PharmD17*, Sandrine Macé, PhD20*, Mony Morisse, MD, MSc21* and Irene Ghobrial, MD22

1University Hospital of Salamanca/IBSAL/Cancer Research Center-IBMCC (USAL-CSIC), Salamanca, Spain
2Servicio de Hematología y Hemoterapia, Clínica Universidad de Navarra, Pamplona, Spain
3Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea, Republic of (South)
4H12O-CNIO Clinical Research Unit, CIBERONC, Department of Hematology, Hospital 12 de Octubre, Complutense University, Madrid, Spain
5Illawarra Cancer Care Centre, Wollongong, NSW, Australia
6Cancer Immunology and Molecular Oncology, Epworth Healthcare, University of Melbourne, Melbourne, VIC, Australia
7Clinical Haematology Service, St. Vincent’s Hospital, Melbourne, VIC, Australia
8Department of Hematology, University Hospital La Fe, Valencia, Spain
9Department of Hematology, Zealand University Hospital, Roskilde, Denmark
10Department of Hematology and Oncology, Clínica São Germano, São Paulo, Brazil
11Department of Internal Medicine, Division of Hematology, Istanbul University Medical Faculty, Istanbul, Turkey
12Division of Hematology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, Republic of (South)
13Service d'Hématologie et Thérapie Cellulaire, CHU and CIC Inserm 1402, Poitiers Cedex, France
14Hematology, Oncology and Transfusion Medicine Department, Vilnius University Hospital, Vilnius, Lithuania
15Oslo Myeloma Center, Department of Hematology, Oslo University Hospital, Oslo, Norway, and KG Jebsen Center for B Cell Malignancies, University of Oslo, Oslo, Norway
16Department of Hematology, Medipol University, Istanbul, Turkey
17Excelya, Boulogne-Billancourt, France
18Sanofi, Research and Development, Vitry-Sur-Seine, France
19Aixial, Boulogne-Billancourt, France
20Sanofi, Vitry-Sur-Seine, France
21Sanofi, Cambridge
22Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Background: Results from a randomized, Phase 3 study by the Spanish Myeloma Group (PETHEMA/GEM) previously showed that treatment with lenalidomide plus dexamethasone (Rd) may delay progression to active disease in patients (pts) with high-risk smoldering multiple myeloma (SMM), compared with observation. To further improve outcomes, addition of the anti-CD38 antibody isatuximab (Isa) to lenalidomide and dexamethasone (Isa-Rd) for the treatment of pts with high-risk SMM is being evaluated in the ongoing, randomized, multi-center, Phase 3 ITHACA study (NCT04270409). Initial findings from the safety run-in analysis of this trial have shown a manageable safety profile and encouraging, preliminary anti-myeloma activity. We now report updated safety and efficacy results from the safety run-in part of ITHACA at a median follow-up of 19.4 months.

Methods: Pts were included in the study if they had been diagnosed within 5 years with SMM (per the International Myeloma Working Group [IMWG] criteria) and had high-risk SMM according to the Mayo ‘20-2-20’ and/or updated PETHEMA model criteria. Pts who had received prior anti-myeloma treatment were not eligible. Enrolled pts received Isa 10 mg/kg IV on day (D) 1, 8, 15, and 22 in cycle (C) 1, D1 and D15 C2–12, D1 C13–36; plus R D1–21 (25 mg C1–9; 10 mg C10–24) and d weekly (40 mg, 20 mg for ≥75 yr-old pts C1–9; 20 mg C10–24). Cycle duration was 28 days. Safety evaluations included treatment-emergent AEs (TEAEs)/serious AEs and laboratory parameters, graded by NCI-CTCAE v5.0. Response was determined by IMWG criteria (2016). Mandatory imaging by MRI and/or low-dose whole-body CT/PET-CT, and assessments of minimal residual disease (MRD, by next-generation sequencing in pts with very good partial response [VGPR] or better), were performed at protocol-defined time points. The primary study objective for the safety run-in was to confirm the recommended dose of Isa in combination with Rd. Overall response rate (ORR) and MRD negativity rate at 10-5 sensitivity were included as secondary endpoints.

Results: At data cut-off (May 9, 2022), 23 pts (median age, 63 [range, 28–85] years) had received Isa 10 mg/kg once weekly then biweekly (QW–Q2W), in combination with Rd. Two (9%) pts met the Mayo clinical model criteria, 13 (57%) pts the updated PETHEMA model criteria and 8 (35%) pts both models’ criteria for high-risk SMM. No pt had a focal lesion on MRI. The median duration of treatment exposure was 19.7 (range, 3.7–22.1) months with a median of 20 (range, 4–24) cycles. Grade ≥3 TEAEs were reported in 11 (47.8%) pts: Covid-19 pneumonia (n=3), insomnia (n=3), and pneumonia, hyperglycemia, agitation, lethargy, gastroesophageal reflux disease, retinal detachment, papular rash, and muscle spasms (n=1 each). No pt died or definitively discontinued treatment due to a TEAE. Serious TEAEs were Covid-19 pneumonia (n=3, grade ≥3), pneumonia (n=1, grade ≥3), and radicular pain, musculoskeletal chest pain, reactive arthritis, pyrexia, and amyloidosis (disease progression) (n=1 each, grade <3). The most common TEAEs (generally of grade 1–2) were insomnia (44%), constipation (30%), peripheral edema (30%), and headache (26%). Infusion reactions occurred in 2 pts (8.7%) (grade 2, infusion day 1, cycle 1). Grade ≥3 treatment-related TEAEs were reported in 9 (39.1%) pts and serious treatment-related TEAEs in 2 (8.7%) pts. Grade 3–4 neutropenia occurred in 7 (30%) pts (grade 4 in 1 [4%] pt) and grade 3 thrombocytopenia in 1 (4%) pt (no grade 4), with no treatment discontinuations due to neutropenia or thrombocytopenia. Responses deepened over time versus the initial analysis, with an ORR of 100% at a median follow-up of 19.4 (range, 18.5–19.5) months: 13.0% of pts reached a stringent complete response (sCR), 30.4% a CR, and 30.4% a VGPR. Results of the MRD assessments will be presented depending on data availability.

Conclusions: Updated results from the safety run-in part of the ITHACA trial continue to show a manageable safety profile for Isa-Rd in pts with high-risk SMM, with no definitive treatment discontinuations due to a TEAE. At a median follow-up of 19.4 months, treatment with Isa-Rd has shown promising efficacy (sCR/CR in 43.5% and ≥VGPR in 73.9% of pts), thus further confirming the recommended dose of Isa (10 mg/kg QW–Q2W) for the randomized part of the study, currently evaluating efficacy and safety of Isa-Rd vs Rd in pts with high-risk SMM.

Clinical trial registration: NCT04270409. Funding: Sanofi.

Disclosures: Mateos: Bristol Myers Squibb/Celgene: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero: Oncopeptides: Other: Advisory board participation ; Pfizer: Other: Advisory board participation ; Kite Pharma: Other: Advisory board participation ; AbbVie: Other: Advisory board participation ; Regeneron: Honoraria; Sanofi: Honoraria, Other: Advisory board participation; GSK: Honoraria, Other: Advisory board participation ; Amgen: Honoraria; Janssen: Honoraria, Other: Advisory board participation ; BMS-Celgene: Honoraria, Other: Advisory board participation ; Consultant in Hematology Clínica Universidad de Navarra: Current Employment; Janssen, BMS, Sanofi, Pfizer, GSK: Consultancy; Amgen, Sanofi, GSK, Janssen, BMS-Celgene, Regeneron: Speakers Bureau. Koh: Proteina: Current holder of stock options in a privately-held company; Curocell: Current holder of stock options in a privately-held company; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Consultancy; GenomeOpinion: Current equity holder in private company; Sanofi Genzyme: Research Funding; BMS: Consultancy; Amgen: Speakers Bureau. Martinez-Lopez: Bristol Myers Squibb: Consultancy, Honoraria, Other: Support for attending meetings and/or travelIncyte; Incyte: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Support for attending meetings and/or travel ; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel ; Roche: Consultancy, Honoraria, Other: Support for attending meetings and/or travel ; Sanofi: Consultancy, Honoraria, Other: Support for attending meetings and/or travel . Parmar: Bristol Myers Squibb: Other: Advisory board participation, Research Funding; Janssen: Other: Advisory board participation; Sanofi: Other: Advisory board participation. Quach: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: receipt of free drug for investigator-initiated study, Research Funding; CSL: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: leadership or fiduciary role , Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: receipt of free drug for investigator-initiated study, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: leadership or fiduciary role, receipt of free drug for investigator-initiated study , Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: leadership or fiduciary role, receipt of free drug for investigator-initiated study , Research Funding. Hermansen: Amgen: Honoraria; Janssen-Cilag: Honoraria, Other: Advisory board participation; Bristol Myers Squibb: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Conference participant support. Hungria: Bristol Myers Squibb: Honoraria; Amgen: Honoraria; GSK: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Takeda: Honoraria. Kim: Alexion, AstraZeneca Rare Disease: Other: Received fees. Leleu: Takeda: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Amgen, Merck, BMS, GSK, Janssen, Oncopeptide, Takeda, Roche, Novartis, AbbVie, Sanofi, Gilead, Pfizer, Harpoon Therapeutic, Regeneron, Iteos: Consultancy, Honoraria; BMS: Honoraria; Janssen: Honoraria; Amgen, BMS/Celgene, Janssen, Takeda, Novartis, Sanofi, Merck, Oncopeptide, Karyopharm, Roche, Abbvie, Carsgen, GSK, and Harpoon Therapeutics: Honoraria. Schjesvold: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Skylite DX: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Targovax: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sevindik: AbbVie: Honoraria, Other: Support for attending meetings and/or travel; Amgen: Honoraria, Other: Support for attending meetings and/or travel ; Bristol Myers Squibb: Honoraria; Deva: Honoraria, Other: Support for attending meetings and/or travel; Erkim: Honoraria, Other: Support for attending meetings and/or travel; Janssen: Honoraria, Other: Support for attending meetings and/or travel; Pfizer: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Support for attending meetings and/or travel. Lavrova: Excelya: Current Employment. Dubin: Sanofi: Current Employment. Devisme: Aixial: Current Employment. Lepine: Excelya: Current Employment. Macé: Sanofi: Current Employment. Morisse: Sanofi: Current Employment. Ghobrial: Vor Biopharma: Honoraria; The Binding Site: Honoraria; Takeda: Honoraria; Sognef: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Veeva Systems: Honoraria; Window Therapeutics: Other: Advisory board participation; Pfizer: Honoraria; Oncopeptides: Honoraria; Menarini Silicon Biosystems: Honoraria; Huron Consulting: Honoraria; GSK: Honoraria; Bristol Myers Squibb: Honoraria; Aptitude Health: Honoraria; Amgen: Honoraria; Adaptive: Honoraria; AbbVie: Honoraria; Novartis: Research Funding; Celgene: Research Funding.

OffLabel Disclosure: Investigational use of isatuximab in patients with high-risk smoldering multiple myeloma

*signifies non-member of ASH