Impact of ixazomib‐lenalidomide‐dexamethasone therapy on overall survival in multiple myeloma patients: Analysis of the emerging‐markets subgroup of the TOURMALINE‐MM1 trial

Abstract Ixazomib‐lenalidomide‐dexamethasone (ixazomib‐Rd) showed clinical efficacy over placebo‐Rd in patients with relapsed/refractory multiple myeloma (MM) in the TOURMALINE‐MM1 trial. Over a median follow‐up of ∼85 months, as patients showed disease progression, they received subsequent novel therapies that confounded the overall survival (OS) benefit. Here, we conducted a post hoc analysis in 148 patients from seven countries defined as emerging markets, with limited access to novel therapies for MM during the trial period, to describe the impact of these therapies on OS. Patients were randomised to ixazomib‐Rd (n = 71) or placebo‐Rd (n = 77). The median progression‐free survival (PFS) was 18.7 versus 10.2 months, with ixazomib‐Rd versus placebo‐Rd (hazard ratio [HR], 0.504; p = 0.008) demonstrating a statistically significant improvement as observed in the primary trial. The median OS improved by 32.6 months with ixazomib‐Rd over placebo‐Rd (63.5 vs. 30.9 months; HR, 0.794; p = 0.261); however, the statistically significant benefit seen in PFS was not observed for OS. Improvement with ixazomib‐Rd over placebo‐Rd was observed in overall response (81.7% vs. 64.9%; odds ratio [OR], 2.38; p = 0.019) and complete response (22.5% vs. 3.9%; OR, 7.57; p < 0.001). Patient‐reported quality of life and use of subsequent therapies were similar across treatment groups. No new safety concerns were identified. Compared with the main cohort, median OS was 10 months longer with ixazomib‐Rd and 21 months shorter with placebo‐Rd in this subgroup, indicating a clinically meaningful survival benefit of ixazomib‐Rd treatment in this patient population with limited access to subsequent novel therapies.


Introduction
Multiple myeloma (MM) is a cancer of the plasma cells characterised by anaemia, bone destruction, fatigue, hypercalcaemia and renal failure [1]. In 2020, more than 150,000 new cases of MM were diagnosed worldwide, and more than 100,000 deaths were recorded [2]. Australia and New Zealand are amongst countries with the highest agestandardised incidence rate (ASIR) of MM in the world at 5 and 4.4 per 100,000 persons, respectively, while China has a low ASIR at 0.9 per 100,000 persons [3]. Although patients with newly diagnosed MM respond well to therapy, a large proportion become refractory during therapy or relapse afterwards. Administration (FDA) [5,6] and in 2016 by the European Medicines Agency (EMA) [7,8], while isatuximab was approved by both the FDA and EMA in 2020 [9,10]. The availability of these drugs was limited before 2020 in the Asia Pacific, the Middle East, Eastern Europe and Latin America.
Clinical trials have shown that PIs are effective for treating patients with newly diagnosed, high-risk MM, and these agents are currently the established regimen for relapsed or refractory (RR) MM in combination with IMiDs and corticosteroids [4]. Ixazomib, the first oral PI, was approved by the FDA in 2015 in combination with lenalidomidedexamethasone (Rd) for patients with MM who have received at least one prior therapy [11]. The pivotal global phase III TOURMALINE-MM1 trial demonstrated that ixazomib-Rd led to a significant improvement in progression-free survival (PFS) over placebo-Rd (median, 20.6 vs. 14.7 months; hazard ratio [HR], 0.74; p = 0.01) [12]. However, the subsequent final overall survival (OS) analysis of the TOURMALINE-MM1 trial showed no significant improvement with ixazomib-Rd versus placebo-Rd in the overall population (median, 53.6 vs. 51.6 months; HR, 0.939; p = 0.495). The OS benefit in the overall population was confounded by the use of subsequent therapy (≥70% of patients).
Specifically, PIs and daratumumab were administered more frequently in the placebo-Rd group due to earlier disease progression compared with that in the ixazomib-Rd group. Moreover, greater OS benefit with ixazomib-Rd over placebo-Rd was observed in patients who did not receive subsequent therapy compared with those who did [13].
The China Continuation study, a distinct regional expansion of the trial. Full details of the study design, eligibility criteria and patient disposition have been described earlier [12,13]. Briefly, the trial included patients ≥18 years of age with relapsed, refractory or relapsed and refractory MM who had received 1-3 prior lines of therapy. Patients who were refractory to prior lenalidomide-or PI-based therapy were excluded [13].
For the TOURMALINE-MM1 global trial, patients were randomly assigned 1:1 to receive ixazomib-Rd or placebo-Rd using a centralised interactive voice response system (IVRS). The dosage and administration schedule have been described earlier [12].

Statistical analyses
The ITT population included all patients from emerging markets who were randomised. The safety population included all patients who received at least one dose of the study drug or placebo. Formal hypothesis testing was not conducted. OS and PFS were evaluated using a closed sequential testing procedure [13] and assessed using the Kaplan-Meier methodology. Treatment groups were compared using a stratified Cox model to estimate the HRs and 95% confidence intervals (CIs) with two-sided, stratified log-rank tests for p values. Response rates were compared using a stratified Cochran-Mantel-Haenszel test, and odds ratios (ORs) were estimated using a logistic regression model.

Demographics and baseline clinical characteristics
This subgroup analysis included 148 patients (median age 63 years; 55% male; 77% white) from seven countries (emerging markets) who received either ixazomib-Rd (n = 71) or placebo-Rd (n = 77). Patient characteristics were well balanced between treatment groups. Highrisk cytogenetic abnormalities occurred in 22% of patients in the ITT population and were similarly distributed in the two treatment groups.
The EORTC QLQ-C30 global health status/QoL subscale scores and the EORTC QLQ-MY20 scores for disease symptoms and side effects of treatment subscales were similar between the ixazomib-Rd and placebo-Rd groups over the course of the follow-up ( Figure S1).

Safety
The safety population included 70 patients in the ixazomib-Rd group and 77 in the placebo-Rd group. One patient in the ixazomib-Rd group received the study drug but did not complete the treatment and was removed from the safety population. The treatment duration was similar for the ixazomib-Rd and placebo-Rd groups: a median of 13 and 12 cycles of treatment with a median exposure of 361 and 327 days, respectively (Table S1). The rates of drugrelated serious AEs, discontinuation of the study regimen because of AEs and death during the treatment period were similar between the ixazomib-Rd and placebo-Rd groups (

Discussion
This post hoc subgroup analysis of the TOURMALINE-MM1 trial aimed to evaluate survival benefit with ixazomib-Rd over placebo- Abbreviations: CI, confidence interval; CR, complete response; DOR, duration of response; ITT, intent-to-treat; NE, not estimable; ORR, overall response rate; PR, partial response, Rd, lenalidomide and dexamethasone; TTP, time to disease progression; VGPR, very good partial response. a Best response after X cycles represents the best confirmed or unconfirmed response within X cycles for all ITT patients. The timeframe is from cycle 1 day 1 (C1D1) to cycle X C(X+1)D1 or end of treatment, whichever comes earlier. Percentages are based on the total number of patients in the ITT population who reached the C(X+1)D1 visit or discontinued. b ORR is defined as the proportion of ITT patients who achieved PR or better, estimated as ORR = CR+VGPR+PR. c VGPR is a subset of PR. VGPR is defined as serum and urine M-protein being detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level of <100 mg per 24 h. d CR is defined as no detection of M-protein in the serum and urine, disappearance of soft-tissue plasmacytomas and <5% of plasma cells in the bone marrow. e Stringent CR is a subset of CR. Criteria for a stringent CR include the criteria for a CR plus a normal free light chain ratio and absence of clonal plasma cells, as assessed using immunohistochemical analysis or immunofluorescence. f PR is defined as reduction of serum M-protein by ≥50% and urine M-protein by ≥90% (<200 mg per 24 h) and ≥50% reduction in the size of soft-tissue plasmacytomas. g Stable disease is defined as the response not meeting any of the criteria for CR, PR, VGPR or progressive disease. h DOR was measured as the time from the date of first documentation of PR or better to the date of first documented progression.

CONCLUSION
Overall, patients with RRMM from emerging markets showed a clinically meaningful benefit in survival with ixazomib-Rd compared with placebo-Rd, with no new toxicity or safety signals. Ixazomib-Rd, an all-oral triplet regimen, represents an effective and well-tolerated treatment option for patients with RRMM, particularly in countries where novel treatment options are limited.

AUTHOR CONTRIBUTIONS
Andrew Spencer contributed to data collection. Olga Samoilova con-

DATA SHARING STATEMENT
The datasets, including the redacted study protocol, redacted statistical analysis plan and individual participants data supporting the results reported in this article, will be made available within three months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymisation.

ETHICS STATEMENT
The study was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and appropriate regulatory requirements. The study was approved by the local ethics committees or institutional review boards at each centre. All patients provided written informed consent.