A phase 1, multicenter study evaluating the safety and efficacy of KITE-585, an autologous anti-BCMA CAR T-cell therapy, in patients with relapsed/refractory multiple myeloma

Abstract

Despite advances in treatment, most patients with multiple myeloma (MM) will relapse, and long-term survival remains poor. B-cell maturation antigen (BCMA) is an ideal therapeutic target as it is expressed throughout the disease course with normal tissue expression limited to plasma and some B-cell lineages. This phase 1, multicenter, first-in-human study evaluated the safety and efficacy of KITE-585, an autologous anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory MM (RRMM). Key eligibility criteria included measurable MM and progression, defined by the International Myeloma Working Group Consensus Criteria within 60 days of the last treatment. Patients underwent leukapheresis and subsequently received a 3-day conditioning therapy regimen (cyclophosphamide [300 mg/m2/day] and fludarabine [30 mg/m2/day]). Patients then received a flat dose of 3 × 107 to 1 × 109 KITE-585 CAR T cells in a 3+3 dose-escalation design. The primary endpoint was incidence of adverse events (AEs) defined as dose-limiting toxicities (DLTs). Key secondary and exploratory endpoints included efficacy outcomes, incidence of AEs, levels of KITE-585 in blood, serum cytokines, and incidence of anti-BCMA CAR antibodies. Seventeen patients were enrolled, and 14 received KITE-585 with a median follow-up of 12.0 months. The median age of patients was 56 years, 41.2% had an Eastern Cooperative Oncology Group performance status of 1, 92.9% had baseline BCMA expression on plasma cells, and median number of prior therapies was 5.5. No patients experienced a DLT, all patients experienced ≥ 1 grade ≥ 3 treatment-emergent AE (TEAE), and no grade 5 TEAEs were observed. There were no grade ≥ 3 events of cytokine release syndrome, neurologic events, or infections; all were grade 1 or 2, and each occurred in 21.4% of patients. Among all patients infused with KITE-585, 1 patient who received 3 × 107 anti-BCMA CAR T cells experienced a partial response. Median peak CAR T-cell expansion was low (0.98 cells/μL), as were median peak serum levels of CAR-associated cytokines, including interferon-γ (61.45 pg/mL) and interleukin-2 (0.9 pg/mL). KITE-585 demonstrated a manageable safety profile; however, the limited CAR T-cell expansion and associated lack of anti-tumor response in patients with RRMM treated with KITE-585 is consistent with the minimal CAR T-cell activity observed.

Keywords: B-cell maturation antigen; Chimeric antigen receptor T cell; relapsed/refractory multiple myeloma.

Conflict of interest statement

R.F.C. has employment with AbbVie; honoraria from Karyopharm, Takeda, and GlaxoSmithKline; and consultancy or advisory role for Karyopharm, Takeda, and GlaxoSmithKline. M.R.B: honoraria from Kite, a Gilead Company, Incyte, Celgene, Sanofi, Novartis, Bristol Myers Squibb, and Agios; consultancy or advisory role for Novartis, Kite, a Gilead Company, CRISPR Therapeutics, Agios, Iovance, Bluebird Bio, WindMIL Therapeutics, and Arcellx; speakers’ bureau participation for Kite, a Gilead Company, Agios, Incyte, Sanofi, and Bristol Myers Squibb; research funding from Kite, a Gilead Company, Novartis, CRISPR Therapeutics, Arcellx, Autolus, Immatics, Triumvira, and Tmunity; and travel support from Kite, a Gilead Company, Novartis, Bristol Myers Squibb, Agios, and Incyte. S.K. has a consulting or advisory role for AbbVie, Celgene, Janssen, Takeda, Adaptive Biotechnologies, Kite, a Gilead Company, and Medimmune/AstraZeneca; research funding from AbbVie, Celgene, Janssen, Takeda, Adaptive Biotechnologies, Kite, a Gilead Company, Medimmune/AstraZeneca, Merck, Novartis, Roche, and Sanofi; other relationship with Oncopeptides Independent Review Committee. S.A.G. has a consulting or advisory role with Kite, a Gilead Company, Novartis, Amgen, Celgene, Sanofi, Pfizer, Miltenyi, Bristol Myers Squibb, GlaxoSmithKline, and Actinium; and research funding from Amgen, Celgene, Sanofi, Pfizer, Actinium, Bristol Myers Squibb, and Miltenyi. A.K.N. has a consulting or advisory role with Takeda, Amgen, Janssen, Bristol Myers Squibb, GlaxoSmithKline, Sanofi, Karyopharm, Adaptive, and Oncopeptides. S.M.L. has a consulting or advisory role for Bristol Myers Squibb; speakers’ bureau participation for Takeda; research funding from Bristol Myers Squibb, Takeda, Janssen, BioLineRx, and Novartis; and travel support from Bristol Myers Squibb. F.L.L. has a consulting or advisory role for Kite, a Gilead Company, Novartis, Amgen, Celgene/Bristol Myers Squibb, GammaDelta Therapeutics, Iovance, Bluebird Bio, Wugen Inc., Calibr, Cellular Biomedicine Group Inc., and Allogen; and research support from Kite, a Gilead Company. N.S.R. has a consulting or advisory role for Bristol Myers Squibb, Bluebird Bio, Takeda, and Amgen; and research funding from Bluebird Bio. L.L. has employment with Lei Lei LLC; leadership role with Lei Lei LLC, stock or other ownership in Amgen; and consulting or advisory role with Kite, a Gilead Company, and BeiGene. J.D. has employment with Kite, a Gilead Company; consultancy or advisory role for GliaCure/Tufts; and patents, royalties, or other intellectual property from Patent US8598141 (Dec 03, 2013). J.B.L. has employment with Kite, a Gilead Company, and stock or other ownership in Gilead and Allogene. J.M.R. has employment with Kite, a Gilead Company. R.Z.O. has stock or other ownership in Asylia Therapeutics; patents, royalties, other intellectual property from MD Anderson and Asylia Therapeutics; research funding from BioTheryX, CARsgen Therapeutics, Celgene, Exelixis, Janssen, Sanofi, and Takeda; advisory board membership for Amgen, Bristol Myers Squibb, Celgene, EcoR1 Capital, Forma, Genzyme, GlaxoSmithKline Biologicals, Ionis Pharmaceuticals, Janssen, Juno, Kite, a Gilead Company, Legend, Molecular Partners, Regeneron, Sanofi, Servier, and Takeda; and consultancy or advisory role for STATinMED Research.

AJCR Copyright © 2021.

Figures

Figure 1

KITE-585 anti-BCMA CAR T cells and select cytokines over time by patient and cohort. A. The number of anti-BCMA CAR T-cells/µL in blood by patient and cohort (n=14). B-E. Levels of serum cytokines over time by patient and cohort (n=14). BL, baseline; BCMA; B-cell maturation antigen; CAR, chimeric antigen receptor; D, day; IFN, interferon; IL, interleukin; Wk, week.