Ixazomib in combination with lenalidomide and dexamethasone significantly delays disease progression in patients with relapsed/refractory multiple myeloma

Data from the phase I II TOURMALINE-MM1 study demonstrate that adding ixazomib, an oral proteasome inhibitor, to standard treatment for relapsed, or treatment-resistant multiple myeloma (RRMM) significantly increases the progression-free survival (PFS). Interestingly, this PFS advantage of adding ixazomib was also observed in the subgroup of patients with high-risk cytogenetics. As such, ixazomib in combination with lenalidomide and dexamethasone represents the first all-oral treatment for multiple myeloma.

The feasibility of combining ixazomib with lenalidomide-dexamethasone (Rd) in an all-oral triplet regimen was first evaluated in a phase I/II trial including 65 patients with newly diagnosed MM. Results of this early phase study indicated an impressive overall response rate (ORR) of 90%, with 62% of patients achieving a very good partial response (VGPR) or better. Moreover, the toxicity profile of this triplet regimen was shown to be manageable. These findings formed the rationale for a large, randomized phase III study, comparing the ixazomib-Rd combination with placebo-Rd in patients with RRMM.

In the study at hand, a total of 722 patients with RRMM, who previously received 1-3 lines of therapy and who were not refractory to prior lenalidomide or a proteasome inhibitor-based therapy, were randomized 1:1 to receive ixazomib (4 mg weekly on days 1, 8, and 15), or matching placebo plus lenalidomide (25 mg on days 1–21) and dexamethasone (40 mg PO on days 1, 8, 15, and 22) in 28-day cycles. The primary endpoint of the study was PFS as assessed by an independent review committee, while secondary objectives included overall survival (OS), and OS in the subgroup of high-risk patients harboring a deletion of chromosome 17.

The median age of participants in the study was 66 years. In total, 19% of the patients in the study were shown to have high-risk cytogenetics (del(17), t(4;14), or t(14;16)), including 10% of patients with a del(17). Of the patients in the study, 69% previously received bortezomib, 45% was previously treated with thalidomide and 12% received lenalidomide before. After a median follow-up of approximately 15 months, the primary endpoint of the study was met. The median PFS in patients receiving the ixazomib combination was 20.6 months as compared to 14.7 months in the placebo-Rd arm (HR [95%CI]: 0.742 [0.587-0.939]; p= 0.012). Interestingly, the median PFS in the subgroup of patients with high-risk cytogenetics treated with ixazomib-Rd was similar to what was seen in the overall patient population. In fact, the median PFS with ixazomib-Rd in the patients with standard risk cytogenetics was 20.6 months, while in patients with high-risk cytogenetics the median PFS was 21.4 months. In the subgroup of high-risk patients, adding ixazomib to Rd resulted in a 45% decrease in the risk of disease progression (median PFS: 21.4 vs. 9.7 months; HR: 0.543). In patients with a del(17) the median PFS was 21.4 months with ixazomib-Rd compared to 9.7 months with placebo-Rd (HR: 0.596).

These data indicate that ixazomib seems to overcome the negative impact of cytogenetic alterations in RRMM. In the discussion following the presentation, some questions were asked concerning the low threshold used for del(17) positivity in the study. However, Professor Moreau countered this by stating that the HR in favor of ixazomib-Rd was similar when the analysis was done in patients with a del(17) in at least 60% of plasma cells. The confirmed rate of ORR was significantly higher with ixazomib-Rd as compared to placebo-Rd: 78.3% vs. 71.5% (p= 0.035). Looking at the rate of complete and very good partial responses, the advantage with ixazomib was even more striking at 48.1% with ixazomib-Rd vs. 39% with placebo-Rd (p= 0.014). Of note, the median time to response with the ixazomib combination was very short at 1.1 months (versus 1.9 months with placebo-Rd). The median duration of response was 20.5 months with ixazomib-Rd versus 15.0 months with placebo-Rd.

Overall, the toxicity rate was similar in both treatment groups, with 68% of the patients in the ixazomib arm suffering from severe but not life-threatening adverse events (grade 3 or higher) compared to 61% of the patients in the placebo group. The rates of treatment discontinuation were also similar for both arms: 13% with ixazomib-Rd and 11% with placebo-Rd. The most common grade ≥3 adverse events were neutropenia (18% vs. 18%) and thrombocytopenia (12% vs. 5%). Gastrointestinal events included diarrhea (45% vs. 39%, grade 3: 6% vs. 2%), nausea (29% vs. 22%, grade 3: 2% vs. 0%) and vomiting (23% vs. 12%, grade 3: 1% vs. <1%). Peripheral neuropathies (almost all low-grade) were seen in 27% of patients in the ixazomib arm as compared to 22% with placebo-Rd. Finally, an analysis of the quality of life (QoL) in the TOURMALINE study demonstrated that the addition of a third agent to the treatment regimen did not compromise the QoL of patients.

In summary, this study demonstrated that adding ixazomib to standard treatment for RRMM significantly delays the time to progression. Interestingly, this was also the case in the subgroup of patients with high-risk cytogenetic characteristics. As such, this study identifies ixazomib plus lenalidomide and dexamethasone as the first safe and effective, all-oral treatment for patients with MM.

Reference

Moreau P, Masszi T, Grzasko N, et al. Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (NCT01564537). Presented at ASH 2015, Abstract #727.