A prospective, multicenter, observational study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in Japan

Abstract

Real-world studies permit inclusion of a more diverse patient population and provide more information on the effectiveness of treatments used in routine clinical practice. This prospective, multicenter, observational study investigated the effectiveness and safety of ixazomib plus lenalidomide and dexamethasone (IRd) in 295 patients with relapsed/refractory multiple myeloma (RRMM) in routine clinical practice in Japan. Patients had a median age of 74 years, 80.0% were aged ≥ 65 years, 42.0% had received ≥ 3 lines of prior treatment, and 28.5% were "frail" according to the International Myeloma Working Group frailty score. After a median follow-up of 25.0 months, median progression-free survival (PFS) was 15.3 (95% CI 12.4-19.5) months, while median overall survival was not reached. The overall response rate was 53.9%, and 31.5% of patients had a very good partial response or better. In the subgroup analysis, median PFS was better in patients with 1 versus 2 or ≥ 3 lines of prior treatment (29.0 vs 19.2 or 6.9 months) and paraprotein versus clinical relapse (16.0 vs 7.9 months), but median PFS was not notably affected by frailty score or age group. Dose adjustment was more frequent among patients aged > 75 years, especially early after IRd treatment initiation. Treatment-emergent adverse events (TEAEs) of any grade occurred in 84.4% of patients and 24.7% of patients discontinued treatment due to TEAEs; no new safety concerns were found. These findings suggest that oral IRd triplet regimen is an effective and tolerable treatment option for RRMM patients in real-world settings outside of clinical trials.ClinicalTrials.gov identifier: NCT03433001; Date of registration: 14 February 2018.

Keywords: Effectiveness; Ixazomib; Multiple myeloma; Real-world data; Relapsed/refractory; Safety.

Fig. 1

Dose adjustment during treatment cycles, shown by age group. (a) Proportion of patients who had a dose adjustment for ixazomib and lenalidomide and (b) Sankey diagram showing the initial dose and dose adjustments, with the vertical bars representing various ixazomib dose ranges and the connecting arcs representing the proportion of patients transitioning from one ixazomib dose to the same or different dose in the next treatment cycle

Fig. 2

Kaplan–Meier curves of (a) progression-free survival (PFS) and (b) overall survival (OS) in the full analysis set (N = 295). Median OS was not reached. CI, confidence interval

Fig. 3

Cumulative best response over time in the full analysis set. CR, complete response; PR, partial response; VGPR, very good partial response

Fig. 4

Progression-free survival (PFS) by subgroup according to (a) IMWG frailty score, (b) age, (c) number of prior regimens, (d) baseline disease status, (e) cytogenetic risk and (f) modified cytogenetic risk. ^aClinical relapse was defined as disease recurrence with CRAB (i.e., calcium elevation, renal insufficiency, anemia, and bone abnormalities) symptoms. ^bParaprotein relapse was defined as disease recurrence with elevated M-protein levels but without CRAB symptoms. ^cStandard-risk was defined as the absence of high-risk cytogenetic abnormalities. ^dHigh-risk was defined as the presence of ≥ 1 of t(4;14), t(14;16), or del(17p). ^eModified standard-risk was defined as the absence of expanded high-risk cytogenetic abnormalities. ^fExpanded high-risk was defined as the presence of ≥ 1 of t(4;14), t(14;16), or del(17p), and/or 1q21 gain. CI, confidence interval; IMWG, International Myeloma Working Group; Int, intermediate; NR, not reached

Fig. 5

Forest plot of progression-free survival (PFS) to determine the association of patient baseline factors of interest with PFS with IRd treatment. A univariate Cox proportional hazard model was used to estimate the hazard ratios for risk of PFS. ^aClinical relapse was defined as disease recurrence with CRAB (i.e., calcium elevation, renal insufficiency, anemia, and bone abnormalities) symptoms. ^bParaprotein relapse was defined as disease recurrence with elevated M-protein levels but without CRAB symptoms. ^cHigh-risk was defined as the presence of ≥ 1 of t(4;14), t(14;16), or del(17p). ^dStandard-risk was defined as the absence of high-risk cytogenetic abnormalities. CCI, Charlson Comorbidity Index; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HSCT, hematopoietic stem-cell transplantation; IRd, ixazomib + lenalidomide + dexamethasone

Fig. 6

Forest plot of progression-free survival (PFS) to determine the association of patient baseline factors of interest with PFS with IRd treatment. A multivariate Cox proportional hazard model was used to estimate the hazard ratios for risk of PFS. ^aClinical relapse was defined as disease recurrence with CRAB (i.e., calcium elevation, renal insufficiency, anemia, and bone abnormalities) symptoms. ^bParaprotein relapse was defined as disease recurrence with elevated M-protein levels but without CRAB symptoms. ^cHigh-risk was defined as the presence of ≥ 1 of t(4;14), t(14;16), or del(17p). ^dStandard-risk was defined as the absence of high-risk cytogenetic abnormalities. CCI, Charlson Comorbidity Index; CI, confidence interval; IRd, ixazomib + lenalidomide + dexamethasone