A Multicenter Phase I Dose-Escalation Trial of a Novel Glutaminase Inhibitor Telaglenastat in Combination with Carfilzomib and Dexamethasone in Relapsed and Refractory Multiple Myeloma

Background: c-MYC activation, an early event of multiple myeloma (MM) pathogenesis, upregulates the expression of the glutaminase 1 (GLS1) enzyme, which converts glutamine to glutamate in the mitochondria. Glutamate is required for the biosynthesis of various molecules in the tricarboxylic acid (TCA) cycle that supports mitochondrial respiration. Proteasome inhibitors (PI) are effective therapeutic agents against MM cells. However, PI resistance still develops among MM cells, and these cells favor the increased use of mitochondrial respiration for energy production. Telaglenastat is a first-in-class, orally available, selective, noncompetitive inhibitor of GLS1. Thus, inhibition of GLS1 is a rational molecular strategy for treating PI-resistant MM.

Methods: This study was a phase 1, multicenter clinical trial of telaglenastat in combination with carfilzomib and dexamethasone for patients with relapsed and refractory MM (NCT03798678) previously treated with at least two prior lines of therapy. This trial involved a 3+3 dose escalation design to determine the maximum tolerated dose (MTD) and recommended phase II dosing (RP2D). Carfilzomib was administered on a weekly dosing schedule of days 1, 8, and 15 of a 28-day cycle, along with dexamethasone on days 1, 8, 15, and 22. Telaglenastat was started at a dose level of 400 mg twice daily and increased in subsequent dose levels. Before day 1 of Cycle 1, a 7-day lead-in of telaglenastat monotherapy was administered. This study also evaluated the plasma pharmacokinetic profiles of telaglenastat and carfilzomib when used in combination.

Results: From July 2019 until Dec 2021, 21 patients were accrued to this study. Of the patients accrued, 10 (48%) were male, and 10 (48%) were over 65. The median number of prior lines of therapy received by the patients in this study was 4 (Range: 2 - 8). All patients were previously exposed to a proteasome inhibitor. Most patients (15/21 or 71%) received a prior autologous stem cell transplant. There were four combination dose levels evaluated, with doses of telaglenastat and carfilzomib ranging from 400 mg to 800 mg twice daily and 56 mg/m² to 70 mg/m², respectively. The median number of cycles received by the patients was 8 (Range: 1 - 26). Four patients remain on treatment. 17 (81%) patients were evaluable for dose-limiting toxicities (DLTs) among whom 2 experienced a DLT of persistent grade 3 or higher thrombocytopenia. The most common hematologic grade 3 or higher AEs observed across the different dose levels among all 21 patients were thrombocytopenia (41%), lymphopenia (29%), anemia (24%), and neutropenia (24%). The most common nonhematologic grade 3 or higher AEs observed across the different dose levels were upper respiratory infection (12%) and fatigue (12%). There were no deaths directly attributable to the treatment. Of the 19 patients whose disease responses were evaluable, the best overall response rate was 58% (11/19) (9 partial responses (PR), 1 very good partial response (VGPR), and 1 complete response (CR)). Stable disease (SD) was seen in 32% (6/19) and 11% (2/19) progressed within one therapy cycle. The telaglenastat peak plasma concentration was achieved 2-4 hours after the oral dose, and peak plasma concentration and systemic exposure increased in proportion to the dose. Following infusions of 56 mg/m² of carfilzomib with telaglenastat on Cycle 1, Day 15, the mean C_max and clearance values of carfilzomib were 727 ng/mL and 142 L/hr/m², respectively. Carfilzomib did not appear to alter the telaglenastat pharmacokinetics following concomitant administration.

Conclusions: Telaglenastat was well tolerated in combination with carfilzomib and dexamethasone. More than half of the patients in this heavily pretreated MM population experienced a hematologic response, with most patients tolerating therapy and remaining on study for a prolonged period. Ongoing correlative studies could provide mechanistic insight into which patients could benefit the most from telaglenastat in combination with proteasome inhibitors.

Neparidze:Janssen: Research Funding; GSK: Research Funding. Kumar:AbbVie,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive,: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE,: Research Funding; MedImmune/Astra Zeneca,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck,: Research Funding; Novartis,: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Oncopeptides: Other: Independent review committee. Baz:Takeda: Membership on an entity's Board of Directors or advisory committees; Shattuck labs: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; genentech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria; celgene: Consultancy, Honoraria; karyopharm: Research Funding; Merck: Research Funding.