Elotuzumab Plus Bortezomib and Dexamethasone Versus Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: 2-Year Follow-up
Authors: Palumbo Antonio , Offidani Massimo , Pégourie Brigitte , De La Rubia Javier , Garderet Laurent , Laribi Kamel , Bosi Alberto , Marasca Roberto , Laubach Jacob P. , Mohrbacher Ann , Carella Angelo Michele , Singhal Anil K. , Lynch Mark , Jou Ying-Ming , Jakubowiak Andrzej 
Published: October 2019

Abstract
Introduction: Elotuzumab, an immunostimulatory monoclonal antibody, recognizes Signaling Lymphocytic Activation Molecule F7 (SLAMF7), a protein highly expressed on myeloma cells and natural killer cells. Elotuzumab exhibits a dual mechanism of action by directly activating natural killer cells and initiating antibody-dependent cell-mediated cytotoxicity in myeloma cells, with minimal effect on normal tissues. This Phase 2 open-label study (NCT01478048, CA204-009) compared the efficacy and safety of elotuzumab in combination with bortezomib and dexamethasone (EBd) vs bortezomib and dexamethasone (Bd) alone in patients (pts) with relapsed/refractory multiple myeloma (RRMM). EBd demonstrated significantly longer progression-free survival (PFS) than Bd (9.7 vs 6.9 months; hazard ratio [HR] 0.72; 70% CI 0.59, 0.88; p=0.09). More pts continued on EBd than Bd and early overall survival (OS) data showed increased improvement with EBd.1 Here we report a longer-term follow-up (2 years) on safety and efficacy.
Methods: Pts with RRMM and 1-3 prior therapies were given EBd or Bd in 21-day (Cycles 1-8) or 28-day (Cycle 9+) cycles until disease progression or unacceptable toxicity. Elotuzumab (10 mg/kg IV) was administered weekly for Cycles 1-2, on Days 1 and 11 for Cycles 3-8, then on Days 1 and 15. Bortezomib (1.3 mg/m2 IV/SC) was administered on Days 1, 4, 8, and 11 for Cycles 1-8, then on Days 1, 8, and 15. Dexamethasone 20 mg was administered on non-elotuzumab days, and at 8 mg PO + 8 mg IV on elotuzumab days. The primary endpoint was PFS (ITT population) according to International Myeloma Working Group criteria. The study had 80% power to detect a HR of 0.69 with 103 events. In this proof-of-concept study, a 2-sided 0.30 significance level was specified to test for PFS difference between arms; p≤0.3 was considered significant.
Results: 152 pts with RRMM (median age 66 years) were randomized (77 to EBd and 75 to Bd). Median time since diagnosis was 45 and 44 months in the EBd and Bd arms, respectively. The proportion of pts with prior proteasome inhibitor (PI) use was 51% in the EBd arm and 53% in the Bd arm. At data cut-off (April 16, 2015), 12% and 3% of pts treated with EBd and Bd, respectively, remained on therapy; discontinuation was mainly due to disease progression (56% across treatment arms). Median number of treatment cycles was 12 in the EBd arm and 7 in the Bd arm. HR for PFS was 0.75 (70% CI 0.62, 0.90). 2-year PFS rate (95% CI) was 18% (10%, 28%) and 10% (4%, 18%) for the EBd arm and Bd arm, respectively. Adjusting for prognostic factors, PFS HR (EBd vs Bd) was 0.60 (70% CI 0.48, 0.74; p=0.0116). The median PFS in the EBd arm was 9.9 months vs 6.8 months in the Bd arm. Overall response rate was 65% in the EBd arm vs 63% in the Bd arm. Fifty-four deaths occurred (26 in EBd arm, 28 in Bd arm), mainly due to multiple myeloma. Grade 3/4 adverse events (AEs) were reported in 53 (71%) and 45 (60%) pts in the EBd and Bd arms, respectively. AEs ≥ Grade 3 in ≥15% of pts were thrombocytopenia (7 [9%] in EBd arm; 13 [17%] in Bd arm) and infections (17 [23%] in EBd arm; 11 [15%] in Bd arm). Infusion reactions (all Grade 1-2) occurred in 5% of EBd-treated pts. Updated efficacy and safety data including 2-year OS data will be presented.
Conclusions: This is the first randomized controlled trial of elotuzumab in combination with a PI. Elotuzumab in combination with Bd shows an improvement in PFS, supported by early OS data.1 This longer-term follow-up demonstrates prolonged PFS with elotuzumab plus Bd, and a safety profile consistent over time, with minimal incremental toxicity, compared with Bd alone. Longer-term data on PFS and OS will be presented, providing insight into the durability of response with EBd vs Bd.
Reference:
1. Jakubowiak A et al. Haematologica 2015;100(s1):2
Study funding: Study funded by Bristol-Myers Squibb and AbbVie Biotherapeutics. Writing assistance was provided by Sarah Addison, PhD, at Caudex and funded by Bristol-Myers Squibb.

Disclosures
Palumbo: Onyx: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Array BioPharma: Honoraria; Sanofi-Aventis: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria. Off Label Use: Elotuzumab is an investigational agent being studied for the treatment of multiple myeloma.. Offidani:Janssen: Honoraria, Other: Travel expenses; Bristol-Myers Squibb: Honoraria, Other: Travel expenses. Garderet:Bristol-Myers Squibb: Consultancy. Laribi:Hospira SAS: Research Funding. Bosi:Celgene: Other: Travel expenses; Alexion Pharmaceuticals: Other: Travel expenses; Teva: Research Funding; Italfarmaco: Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Sandoz: Consultancy; Mundipharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria; Binding Site: Other: Travel expenses. Marasca:Novartis: Honoraria, Other: Travel grant; Roche: Honoraria; Janssen: Honoraria, Other: Travel grant, Research Funding; Celgene: Other: travel grant; Gilead: Honoraria. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Singhal:Abbvie: Employment. Lynch:Bristol-Myers Squibb: Employment. Jou:Bristol-Myers Squibb: Employment. Jakubowiak:Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: institutional funding for support of clinical trial conduct, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.