Elotuzumab Plus Lenalidomide/Dexamethasone (ELd) Vs Ld in Patients with Newly Diagnosed Multiple Myeloma: Phase 2, Randomized, Open-Label Study in Japan

Abstract

Introduction: Elotuzumab, a humanized IgG1 monoclonal antibody that binds to SLAMF7 expressed on myeloma and natural killer (NK) cells, has a dual mode of action; it causes targeted myeloma cell death by directly activating NK cells and enhances NK cell-mediated antibody-dependent cellular cytotoxicity. Elotuzumab combined with lenalidomide and dexamethasone (ELd) has been approved in Japan for the treatment of relapsed/refractory multiple myeloma (RRMM). In a 4-y follow-up of the phase 3 ELOQUENT-2 study (NCT01239797) in patients (pts) with RRMM, ELd demonstrated a sustained 29% reduction in risk of disease progression/death and an overall survival benefit vs Ld (Dimopoulos M et al. Haematologica 2017), consistent with prior reports (Dimopoulos M et al. Br J Haematol 2017). We present the first report on the efficacy/safety of ELd vs Ld in pts with newly diagnosed multiple myeloma (NDMM).Methods: In this phase 2, open-label, multicenter study (NCT02272803) in Japan enrolling pts with NDMM ineligible for high-dose chemotherapy plus hematopoietic cell transplantation, pts were randomized 1:1 to intravenous elotuzumab (10 mg/kg weekly for Cycles 1 and 2; every 2 wk for Cycles 3-18; 20 mg/kg monthly thereafter) plus Ld or Ld alone, in a 28-d cycle until disease progression or unacceptable toxicity. All pts in the ELd arm received premedication prior to elotuzumab to mitigate infusion reactions (IRs). In the absence of IRs, infusion rate was increased from 0.5-2.0 mL/min at dose 1, and up to a maximum of 5 mL/min (per FDA/EMA labels for ELd in RRMM) by dose 3 of Cycle 1. Primary endpoint was investigator-assessed objective response rate (ORR) with ELd, per International Myeloma Working Group criteria (1-sided α=0.15 for a true response rate >71%). Secondary endpoints included difference in ORR between the arms and progression-free survival (PFS). Safety was an exploratory endpoint.Results: In total, 40 and 42 pts received ELd and Ld, respectively. At database lock (March 2017; minimum follow-up of 6 mo), 31 (78%) pts in the ELd arm and 25 (60%) in the Ld arm remained on study. At baseline, median (range) age was 72 y (65-83) in the ELd arm and 73 y (62-89) in the Ld arm. Median duration of therapy was 13.0 cycles with ELd and 11.5 cycles with Ld. The most common reason for discontinuation was: ELd (9 pts)-disease progression (4/40 pts [10%]); Ld (17 pts)-drug toxicity, adverse events (AEs) unrelated to study drug, and pt request (each with 4/42 pts [10%]). The primary endpoint was met: investigator-assessed ORR (Table) was 88% with ELd; lower bound of the 2-sided 70% CI in ORR was 80% (> threshold of 71%). The ORR in the LD arm was 74%. ORR was 13% numerically higher with ELd than Ld. Very good partial response or better was observed for 45% of ELd- and 29% of Ld-treated pts. AEs were reported in 40 (100%) and 41 (98%) pts in the ELd and Ld arms, respectively. The most common (≥20%) AEs for ELd vs Ld included constipation (43% vs 31%), pyrexia (35% vs 7%), rash (28% vs 36%), diarrhea (28% vs 21%), nasopharyngitis (25% vs 26%), dysgeusia (23% vs 19%), malaise (23% vs 2%), peripheral edema (20% vs 14%), neutropenia (20% vs 14%), leukopenia (20% vs 7%), and back pain (18% vs 21%). Grade (G) 3-4 AEs occurred in 31 (78%) and 19 (45%) pts in the ELd and Ld arms, respectively. The most common G3-4 AEs (ELd vs Ld) were neutropenia (18% vs 7%) and leukopenia (15% vs 0%). One IR was reported (ELd): G2 hypersensitivity during the first infusion (2-mL/min infusion rate); elotuzumab infusion was interrupted; the pt did not experience any IRs at subsequent infusions. Thirty-eight pts (95%) received elotuzumab at 5 mL/min (representing 1046/1176 [89%] infusions) and no IRs were reported at this increased infusion rate. Secondary primary malignancies were reported in 1 pt in each arm (of the rectum and lung with ELd and Ld, respectively). ELd had a comparable safety profile when given at 10 mg/kg weekly or every 2 wk up to Cycle 18, or at 20 mg/kg monthly from Cycle 19 onwards. PFS data are not yet mature.Conclusions: In this first report of ELd treatment of pts with NDMM, the primary endpoint of ORR was met. ELd had an acceptable safety profile in this pt population, and an increased infusion rate of 5 mL/min, which reduced infusion time and did not induce additional IRs. These data suggested that ELd with a faster infusion rate of 5 mL/min was effective and well tolerated in Japanese pts with NDMM.Study support: Bristol-Myers Squibb K.K. [Display omitted] DisclosuresOhta:Bristol-Meyer Squibb K.K., Celgene K.K., Jansen Pharmaceutical K.K., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd: Honoraria. Hori:Celgene, Fujifilm RI Pharma, Shire Japan: Other: Post-marketing surveillance study fee. Kinoshita:Bristol-Myers Squibb K.K.: Employment. Shelat:Bristol-Myers Squibb: Employment, Equity Ownership. Miyoshi:Bristol-Myers Squibb K.K.: Employment.