Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China Continuation study

Multiple myeloma (MM) accounts for approximately 13% of hematologic cancers [ 1]. In the USA and European Union, the age-standardized annual incidence is approximately 4.5 to 7 cases per 100,000 population [ 2, 3]; MM is currently less common in Asian countries, but the incidence is increasing [ 4, 5]. In China, the age-standardized annual incidence of MM in 2005 was estimated to be 0.6 per 100,000 [ 6], and the age-standardized mortality rate has been estimated as 0.6 per 100,000 deaths in 2013 [ 5]. A large retrospective analysis of outcomes of Chinese patients indicated that, at diagnosis, patients have more advanced-stage disease, renal dysfunction, and bone destruction compared with Western patients [ 7].

The introduction of novel therapies such as proteasome inhibitors and immunomodulatory drugs has significantly improved survival in MM over the past two decades [ 8]. Outcomes are improving further through the treatment paradigm of long-term or continuous therapy [ 9, 10]. However, despite these improvements, MM remains incurable. New treatment options are needed for patients with relapsed/refractory MM (RRMM), and specific investigation of these therapies in Asian populations is important in the context of differences in the clinical profile of MM and treatment patterns compared with in North America and Europe [ 4].

Ixazomib is the first oral proteasome inhibitor to enter the clinic. It is approved by the US Food and Drug Administration and the European Medicines Agency for use, in combination with lenalidomide and dexamethasone (Rd), for the treatment of patients with MM who have received at least one prior therapy [ 11, 12]. These decisions were based on the global, double-blind, placebo-controlled, randomized phase III TOURMALINE-MM1 study of ixazomib-Rd versus placebo-Rd in 722 patients with RRMM following one to three prior lines of therapy [ 13]. Ixazomib-Rd demonstrated a significant 35% improvement in progression-free survival (PFS) versus placebo-Rd (median 20.6 vs 14.7 months; hazard ratio (HR) 0.74), with limited additional toxicity. As overall survival (OS) data were not mature at the primary analysis, the global study continued in a double-blind, placebo-controlled fashion [ 13].

The global TOURMALINE-MM1 study included only 6 Chinese patients. Thus, a separate regional expansion study—the China Continuation study—was conducted, following the approval of Rd for RRMM by the China State Food and Drug Administration in 2013 [ 14], with the aims of evaluating ixazomib-Rd versus placebo-Rd in a Chinese patient population and of expanding the worldwide information on the addition of ixazomib to Rd in the treatment of RRMM. The China Continuation study had a similar study design to the global study and, as an intended registration study, was executed with the same stringency [ 13].

The randomized, double-blind, placebo-controlled China Continuation study demonstrated that ixazomib-Rd resulted in superior PFS and OS compared with placebo-Rd in Chinese patients with RRMM after one to three prior lines of therapy. Notably, this is the first randomized study in RRMM demonstrating a significant OS benefit with ixazomib-based therapy. The positive treatment effect for the primary endpoint of PFS supports the findings reported from the global TOURMALINE-MM1 study, in which a significant 35% improvement in PFS was demonstrated [ 13]. In the China Continuation study, benefits were seen across the secondary efficacy endpoints of ORR, DOR, and TTP, which were also improved with ixazomib-Rd versus placebo-Rd in the global study [ 13], and findings were consistent with respect to the benefits of renal insufficiency reversal (in patients with creatinine clearance <50 mL/min) and anemia control, and lower rates of renal failure and hypercalcemia (clinical manifestations of MM-related organ dysfunction). Reflecting the global study [ 13], the China Continuation study showed limited additional toxicity with ixazomib-Rd compared to placebo-Rd. These findings thus provide supportive evidence for the activity, tolerability, and safety of the all-oral triplet regimen of ixazomib-Rd in patients with RRMM. Findings from phase III studies of carfilzomib, elotuzumab, and daratumumab in combination with Rd have similarly demonstrated significant efficacy improvements in patients with RRMM but have not yet reached final OS conclusions, with pomalidomide-based regimens also demonstrating notable activity in this setting [ 17]. In the context of balancing safety, efficacy, and convenience, ixazomib-Rd represents an additional treatment option for RRMM patients.

Ixazomib-Rd showed consistent benefit over placebo-Rd in both the China Continuation and global TOURMALINE-MM1 studies, with HRs of 0.598 and 0.742 for PFS, and 0.583 and 0.712 for TTP [ 13], respectively. The studies had identical eligibility criteria, stratification factors, dosing regimens, and efficacy assessment methodologies; however, despite this, median PFS and TTP and response rates in the China Continuation study were lower in both treatment arms than in the global study. These differences are likely attributable to the fact that Chinese MM patients present with more advanced-stage disease, renal dysfunction, and bone destruction than patients in other regions [ 4, 7]; consequently, there were differences in some baseline characteristics associated with prognosis between the China Continuation and global TOURMALINE-MM1 study populations. For example, Chinese patients had a higher rate (37 vs 22% [Millennium Pharmaceuticals, Inc., data on file]) of ISS stage III disease at initial diagnosis and showed a shorter median time from initial diagnosis to study entry (28.7 and 42.8 months, respectively), indicating more aggressive disease. Furthermore, Chinese patients had more adverse disease status at study entry than the global population [ 13] (53 vs 11% refractory; 23 vs 12% relapsed and refractory; 24 vs 77% relapsed) and were more heavily pretreated (56 vs 39% had received two or three prior therapies; 84 vs 45% had prior thalidomide exposure; 63 vs 12% were thalidomide-refractory at study entry), but prior stem cell transplant was substantially less common (17 vs 57%) [ 13]. The presence of high-risk cytogenetic factors is also established as an important prognostic factor in MM that might have affected outcomes [ 18]; however, as described in the “ Statistical analysis” section of the “ Methods” section, a limitation of this study was that cytogenetics information was not available for the majority of patients and is thus not reported.

Of note, there was also a relevant difference in median PFS between the MM-021 study of Rd in Chinese patients with RRMM, in which median PFS was 8.3 months [ 14], and global studies of Rd, in which median PFS was 15–18 months [ 13, 19– 21]. PFS among patients in the placebo-Rd arm of the China Continuation study appeared somewhat shorter than in the MM-021 study of Rd in Chinese patients with RRMM [ 14]; acknowledging the limitations associated with cross-trial comparisons, this discrepancy may have been due to patient population differences and the use of blinded IRC versus investigator assessment of progression.

Importantly, due to the more aggressive nature of MM in Chinese patients, OS data were mature after a shorter follow-up period in the China Continuation versus the global TOURMALINE-MM1 study, in which median OS had not been reached in either arm after a median follow-up of 23 months. Prolonged follow-up is required to elucidate OS benefit in the global study [ 13], whereas these data from the China Continuation study provide an earlier demonstration of the OS benefit with ixazomib-Rd versus placebo-Rd in a patient population with more advanced disease. At the final analysis for OS, after a median follow-up of ~20 months, ixazomib-Rd resulted in a highly significant improvement in OS versus placebo-Rd in Chinese patients with RRMM. Additional analyses suggest that these OS findings are indicative of a treatment effect, rather than an effect driven by imbalances between arms in patient subgroups, subsequent therapies, or non-MM-related deaths. The OS benefit was maintained regardless of whether patients received subsequent therapy, and subsequent therapies were similar between arms as a consequence of the double-blind study design (i.e., no imbalance in use of rescue proteasome inhibition), except for alkylators and other therapies; an OS benefit with ixazomib-Rd was observed in patients both with and without subsequent alkylator use, indicating that asymmetry in subsequent alkylator use was not driving the OS benefit. Notably, outcomes in Chinese patients are not confounded by the broad array of approved and investigational regimens available in North America and Europe, and consequently, subsequent therapy in China is different from in Western populations; this supports the demonstrated OS benefit as a true treatment effect of ixazomib-Rd. Interestingly, OS from the start of subsequent bortezomib was similar in both treatment groups, suggesting that bortezomib-based regimens can be given after ixazomib-based treatment. Finally, the proportion of deaths with myeloma as the primary cause was similar in both arms, indicating no imbalance in other-cause mortality driving the OS benefit. However, it is important to acknowledge that caution is required when interpreting the findings from the present study, including the OS data. A limitation of the study, particularly when interpreting OS in patient subgroups, is the relatively low sample size and the small absolute numbers of events.

Tolerability and safety data from the China Continuation study reinforced findings from the global study showing that ixazomib adds limited toxicity to Rd [ 13]. In Chinese patients, rates of grade ≥3 AEs were similar between arms. Thrombocytopenia was more common in the ixazomib arm, likely associated with the known transient and cyclical decreases in platelet count reported with proteasome inhibition [ 22, 23], and rates of low-grade gastrointestinal toxicities were also higher. The overall rate of herpes zoster with ixazomib-Rd was 21% but only 9% in patients receiving appropriate antiviral prophylaxis, demonstrating the importance of this concomitant medication in this population with advanced disease. Rates of rash and peripheral neuropathy were similar between arms in the China Continuation study, despite being somewhat higher with ixazomib-Rd in the global study [ 13]. There were no cardiac or renal safety signals with ixazomib-Rd in Chinese patients. The differences in relative safety profiles between the China Continuation and global studies may be influenced by differences in AE reporting practices between Chinese and global physicians or differences in treatment exposure; patients had received a median of 9 and 6.5 cycles of ixazomib-Rd and placebo-Rd, respectively, at the final analysis for OS in the China Continuation study, compared with medians of 17 and 15 cycles in the global study [ 13]. However, this shorter treatment duration was not due to poorer tolerability; the rate of discontinuations due to AEs was only 9 and 10% with ixazomib-Rd and placebo-Rd in Chinese patients, respectively, compared with 17 and 14%, respectively, in the global study [ 13].

Similar to what has been observed in other studies [ 24, 25], ixazomib was rapidly absorbed in Chinese patients (median T _max of ~1–2 h post-dose) and exhibited a long t _½ of ~1 week. However, systemic exposures of ixazomib in Chinese patients in this study were higher than exposures observed in other patient populations. Specifically, analysis of pharmacokinetic data from this study using the previously reported population pharmacokinetic model [ 26] demonstrated that mean ixazomib AUC in Chinese patients was 80% higher than in White patients; however, some overlap in the AUC distribution was observed across patient populations (Fig.  4). The reason for the higher systemic exposures in Chinese patients is unclear. Differences in body size are known to exist between Asian and Western patient populations. Based on population pharmacokinetic analyses [ 26, 27], neither weight (range 37–151 kg) nor body surface area (range 1.2–2.7 m ²) was a significant covariate on ixazomib clearance, suggesting that the higher ixazomib exposures observed in Chinese patients are not related to differences in body size. Inter-ethnic differences in the expression and activity of cytochrome P450 (CYP) enzymes or drug transporters have also been reported between Asian and non-Asian patient populations [ 28, 29]; examples include differences in allelic frequencies for CYP2C19, and lower intrinsic activity of the hepatic uptake transporter OATP1B1 in Asian populations compared with non-Asian populations [ 30, 31]. However, at clinically relevant ixazomib concentrations, no specific CYP enzyme predominantly contributes to ixazomib metabolism and ixazomib is not a substrate for hepatic organic anion-transporting polypeptides [ 11]. Therefore, inter-ethnic differences in drug-metabolizing enzymes or transporters are unlikely to explain the higher ixazomib exposures observed in this study. Importantly, although ixazomib systemic exposures were higher in Chinese patients, the 4.0 mg weekly ixazomib dose, in combination with Rd, demonstrated a favorable benefit–risk profile in Chinese patients with RRMM.

The China Continuation study of ixazomib-Rd versus placebo-Rd demonstrated consistent and significant superiority with ixazomib-Rd for the primary endpoint of PFS, with limited additional toxicity. Further, the China Continuation study showed a significant improvement in OS with ixazomib-Rd at the final analysis. These findings support the efficacy and tolerability of this all-oral triplet regimen as a treatment option for patients with RRMM around the world.