Two years of ixazomib maintenance significantly delays disease progression after transplantation in newly diagnosed multiple myeloma

Results of the phase III, randomized TOURMALINE-MM3 trial demonstrate that two years of maintenance therapy with the proteasome inhibitor (PI) ixazomib after an autologous stem cell transplantation (ASCT) for patients with newly diagnosed multiple myeloma (NDMM) is associated with a 28% reduced risk of disease progression or death compared to placebo. Ixazomib maintenance resulted in a 5-month improvement in median progression free survival (PFS) from 21.3 months with placebo to 26.5 months with ixazomib. In addition, ixazomib was associated with more improvements in the depth of response compared to placebo and came with a favorable safety profile. As such, these data identify ixazomib as a new maintenance option for NDMM patients undergoing an ASCT.

Relapse following an ASCT is almost inevitable in multiple myeloma (MM). In this light, maintenance therapy was extensively explored as a strategy to prolong the duration of disease control and potentially survival following ASCT. To date, only lenalidomide has been approved for this indication. However, lenalidomide maintenance is associated with the development of second primary malignancies and tolerability issues. PIs form a backbone of MM treatment and have a different mode of action than lenalidomide. Maintenance therapy with the PI bortezomib demonstrated promising activity post-ASCT, but to date no benefit of PI-based maintenance has been demonstrated in a placebo-controlled phase III trial. Moreover, the feasibility of bortezomib maintenance in routine clinical practice is limited for reasons of toxicity and the need for regular parenteral administration. As such, there is a need for an oral PI maintenance therapy that can be administered for a prolonged period, improve depth of response without cumulative or late-onset toxicity, and improve convenience for patients. To address this medical need, the phase III TOURMALINE-MM3 trial evaluated post-ASCT maintenance therapy with ixazomib in NDMM. Ixazomib represents a particularly interesting option for maintenance therapy given its favorable toxicity profile and the convenient oral dosing.

In the study at hand, 656 NDMM patients, who had at least a partial response (≥PR) to induction therapy with a PI and/or immunomodulatory drug (IMiD) followed by single ASCT, were randomized (3:2) to receive ixazomib or matched placebo on days 1, 8, and 15 of 28-day cycles for up to 2 years or until progressive disease (PD) or unacceptable toxicity. The ixazomib dose was 3.0 mg during cycles 1-4, increasing to 4 mg from cycle 5 if tolerated during cycles 1-4. The primary endpoint was PFS, with OS as a key secondary objective.

Patient demographics were well balanced between groups. The overall median age was 57 years, 37% had ISS I disease, two thirds had an ECOG performance status 0 and 33% of patients was MRD negative at study entry. Seventeen percent of patients harbored high-risk cytogenetic features. The majority of patients (60%) received a PI without an immunomodulatory (IMiD) agent as induction therapy, 30% received an IMiD/PI combination as induction and 11% received an IMiD-based induction regimen without a PI. A complete response (CR) after induction was obtained in 34%, 45% had a very good partial response (VGPR) after induction, and 21% had a partial response (PR).

After a median follow-up of 31 months, there was a 28% reduction in the risk of progression or death, corresponding to a 39% improvement in PFS with ixazomib vs. placebo (median 26.5 vs. 21.3 months; HR[95%CI]: 0.72[0.582-0.890]; p=0.002). The PFS benefit with ixazomib maintenance was seen broadly across subgroups, including patients with ISS III disease (HR: 0.661), PI-exposed patients (HR: 0.750), PI-naïve patients (HR: 0.497), and patients with high-risk cytogenetics (HR: 0.625). The median OS have not yet been reached in either arm.

Ixazomib maintenance also led to higher rates of deepened response compared with placebo: with placebo 32% of patients with a VGPR at study entry improved to a CR, while this was the case for 43% of patients treated with ixazomib (relative risk: 1.41; 95%CI: 1.10-1.80; p=0.004). Similarly, 34% of placebo patients improved from a PR at study entry to a VGPR or CR, while this was observed in 53% of patients in the ixazomib arm. Conversion from documented MRD positivity at study entry to MRD negativity also occurred at a higher rate with ixazomib compared with placebo (12% vs. 7%). Of note, a PFS benefit was observed with ixazomib irrespective of MRD status. Among MRD-negative patients, the median PFS with ixazomib was 38.6 months vs. 32.5 months with placebo, while in MRD-positive patients the medians for PFS were 23.1 and 18.5 months with ixazomib and placebo, respectively.

Ixazomib maintenance was well tolerated with a low rate of treatment discontinuation due to adverse events (AEs) (7% ixazomib vs. 5% placebo). With ixazomib vs. placebo, 42% vs. 26% of patients had grade ≥3 AEs and 27% vs. 20% had serious AEs. Common grade ≥3 AEs were infections (15% vs. 8%), including pneumonia (6% vs. 4%), gastrointestinal disorders (6% vs. 1%), and neutropenia (5% vs. 3%). Peripheral neuropathy was observed in 19% and 15% with ixazomib and placebo, but this hardly ever reached grade 3 in severity (<1% vs. 0%). The rate of second primary malignancies was 3% in both arms. Final, global Quality of Life scores (EORTC QLQ-C30) on ixazomib were similar to what was seen with placebo.

In conclusion, this study demonstrated a 28% reduction in the risk of progression/death, corresponding to a 39% improvement in PFS with ixazomib maintenance, with deepening of responses and increased conversions to MRD negativity over control. Tolerability is of pivotal importance in the maintenance setting and this is adequately addressed by the favorable safety profile of ixazomib, including an absence of risk of second primary malignancies and low rates of peripheral neuropathy. As such, these data support ixazomib as a new maintenance option in responding NDMM patients post-ASCT.

Reference

Dimopoulos M, Gay F, Schjesvold FH, et al. Maintenance therapy with the oral proteasome inhibitor (PI) ixazomib significantly prolongs progression-free survival (PFS) following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (NDMM): phase 3 Tourmaline-MM3 trial. Presented at ASH 2018; Abstract 301.