Oral ixazomib-dexamethasone vs oral pomalidomide-dexamethasone for lenalidomide-refractory, proteasome inhibitor-exposed multiple myeloma: a randomized Phase 2 trial

Abstract

Multiple myeloma (MM) patients typically receive several lines of combination therapy and first-line treatment commonly includes lenalidomide. As patients age, they become less tolerant to treatment, requiring convenient/tolerable/lenalidomide-free options. Carfilzomib and/or bortezomib-exposed/intolerant, lenalidomide-refractory MM patients with ≥2 prior lines of therapy were randomized 3:2 to ixazomib-dexamethasone (ixa-dex) (n = 73) or pomalidomide-dexamethasone (pom-dex) (n = 49) until progression/toxicity. Median progression-free survival (mPFS) was 7.1 vs 4.8 months with ixa-dex vs pom-dex (HR 0.847, 95% CI 0.535-1.341, P = 0.477; median follow-up: 15.3 vs 17.3 months); there was no statistically significant difference between arms. In patients with 2 and ≥3 prior lines of therapy, respectively, mPFS was 11.0 vs 5.7 months (HR 1.083, 95% CI 0.547-2.144) and 5.7 vs 3.7 months (HR 0.686, 95% CI 0.368-1.279). Among ixa-dex vs pom-dex patients, 69% vs 81% had Grade ≥3 treatment-emergent adverse events (TEAEs), 51% vs 53% had serious TEAEs, 39% vs 36% had TEAEs leading to drug discontinuation, 44% vs 32% had TEAEs leading to dose reduction, and 13% vs 13% died on study. Quality of life was similar between arms and maintained during treatment. Ixa-dex represents an important lenalidomide-free, oral option for this heavily pretreated, lenalidomide-refractory, proteasome inhibitor-exposed population.Trial registration: ClinicalTrials.gov number, NCT03170882.

Conflict of interest statement

MAD reports receiving honoraria from Amgen, Takeda, BMS, Janssen, and Beigene. FS reports receiving honoraria from Amgen, Takeda, and Sanofi; consulting/advisory roles for Celgene, Janssen, Oncopeptides, and Sanofi; and research funding from Celgene, Sanofi, Janssen, Oncopeptides, and GSK. VD reports receiving honoraria from Takeda, Sanofi, and Janssen; consulting/advisory roles for Celgene, Janssen, and Sanofi; and research funding from Celgene, Sanofi, Janssen, Agios Pharmaceuticals Inc, and Pfizer. OV reports receiving honoraria from Takeda, Sanofi, Janssen, and BMS; consulting/advisory roles for Celgene, Janssen, Sanofi, and BMS; and research funding from Celgene, Janssen, Sanofi, and BMS. HQ reports consulting/advisory roles for and receiving honoraria from GSK, Sanofi, Janssen Cilag, BMS, Celgene, CSL, Amgen, Takeda, Karyopharm, and Antengene; and research funding from GSK, Amgen, Celgene, Sanofi, and Karyopharm. XL reports receiving honoraria from Janssen, Takeda, Sanofi, Bas, Novartis, Amgen, Oncopeptide, Karyopharm, Incyte, and GSK. YGM reports no conflicts of interest. KR reports consulting/advisory roles for Celgene/BMS, Takeda, Janssen, Amgen, AbbVie, Sanofi, Oncopeptides, Karyopharm, GSK, Adaptive Biotech, and Pfizer; has served on speakers bureaus for Celgene/BMS, and Takeda; has received research funding from Celgene/BMS, Takeda, Janssen, and Amgen; and travel, accommodation and expenses from Celgene/BMS, Takeda, and Janssen. AP has received honoraria and travel, accommodation and expenses from Janssen, Celgene, Takeda, and Amgen. M-DL reports consulting/advisory roles for and receipt of travel, accommodation, and expenses from Takeda, AbbVie, Janssen, Roche, and Amgen. CL reports a consulting/advisory role for Janssen and research funding from BMS. UHM reports receiving honoraria from BMS, Janssen, Sandoz, Takeda, Amgen, and Sanofi; and consulting/advisory roles for Amgen and Oncopeptides. RF reports consulting/advisory roles for and has received honoraria and travel, accommodation, and expenses from BMS/Celgene, GSK, Amgen, and Janssen. HD reports a consulting/advisory role for Novartis, and has received honoraria from Amgen and Novartis, and travel expenses from Janssen. HS has received honoraria from Takeda, Novartis, and Janssen; research funding from Celgene; and travel, accommodation and expenses from Celgene and Takeda. AV, RL, JD and MD are employees of Takeda. SK reports consulting/advisory roles (with no personal payment) for AbbVie, Amgen, BMS, Janssen, Roche-Genentech, Takeda, KITE, and Astra-Zeneca; consulting/advisory roles (with personal payment) for Oncopeptides, Beigene, and Antagene; and has received institutional research funding from AbbVie, Amgen, BMS, Carsgen, Janssen, KITE, Merck, Astra-Zeneca, Novartis, Roche-Genentech, Takeda, and Tenebio.

© 2022. The Author(s).

Figures

Fig. 1. CONSORT diagram.

Patient disposition throughout the study. AE adverse event, dex dexamethasone, ITT intent-to-treat, ixa ixazomib, OS overall survival, PD progressive disease, PFS progression-free survival, pom pomalidomide.

Fig. 2. PFS with ixa-dex vs pom-dex in the ITT population.

A Kaplan–Meier analysis of PFS and (B) Forest plot of PFS in prespecified subgroups based on patient and disease characteristics. ALT alanine aminotransferase, AST aspartate aminotransferase, CI confidence interval, dex dexamethasone, ECOG Eastern Cooperative Oncology Group, HR hazard ratio, ISS International Staging System, ITT intent-to-treat, ixa ixazomib, NE not estimable, PFS progression-free survival, pom pomalidomide, ULN upper limit of normal.

Fig. 3. Kaplan–Meier analysis of TTP and OS with ixa-dex vs pom-dex in the ITT population.

A TTP and (B) OS. CI confidence interval, dex dexamethasone, HR hazard ratio, ITT intent-to-treat, ixa ixazomib, NE not estimable, OS overall survival, pom pomalidomide, TTP time to progression.

Fig. 4. Mean scores over time for EORTC QLQ-C30 domains with ixa-dex vs pom-dex.

Significant differences between arms were seen at multiple time points: (A) cognitive functioning, (B) insomnia, and (C) diarrhea in patients on the ixa-dex and pom-dex arms. C Cycle, D1 Day 1, dex dexamethasone, CI confidence interval, ixa ixazomib, LS least squares, pom pomalidomide. * Indicates P ≤ 0.05.