Response kinetics and treatment outcomes in RRMM

The TOURMALINE-MM1 study proved that superior outcomes occurred in RRMM patients when ixazomib was added to standard lenalidomide-dexamethasone (IRd) therapy. Since the publication of the original trial, several studies have investigated outcomes in various subsets of patients from this dataset.

Maria Victoria Mateos and colleagues studied the impact of prior myeloma therapies on the safety and efficacy of IRd vs Rd. This study revealed that IRd offered clinical benefit to patients regardless of the agents used in prior therapy. However, there was a difference based on the number of prior therapies and stem cell transplant history. Patients who received two or three prior therapies, or one prior therapy without a transplant, fared better than those with one prior therapy who also underwent a transplant.

In a biomarker analysis carried out by Alessandra DiBacco, the relationship of therapy outcomes in RRMM patients was related to tumor gene expression patterns.  This specifically explored the impact of c-MYC expression in patients from the TOURMALINE-MM1 study. A significant benefit in progression-free survival (PFS) was seen in patients with high c-MYC expression in the IRd arm, compared to those receiving only Rd therapy.

An additional analysis of outcomes in TOURMALINE-MM1 patients with high-risk cytogenetics was conducted by Herve Avet-Loiseau. High-risk cytogenetics included del(17p), t(4;14), t(14;16) and the 1q21 amplification. This multi-national study found that patients with both high- and standard- risk cytogenetics had an improved PFS when ixazomib was added to lenalidomide-dexamethasone.

The most recent subgroup analysis of TOURMALINE-MM1 was carried out by Laurent Garderet from the Hospital Saint Antione in Paris, which examined the association of response kinetics and outcomes, and the findings were published in Leukemia in March 2018. The goal of this study was to determine the long-term outcomes in RRMM patients based on early (0–4 months) vs late (> 4 months) treatment responses.

Key Findings:

• Outcomes by Independent Review Committee-assessed best-confirmed response; N = 676 patients (pts)
  • Stringent complete response (sCR) = 2%
  • Complete response (CR) = 11%
  • Very good partial response (VGPR) = 38%
  • Partial response (PR) = 30%
  • Stable disease (SD) = 13%
  • Progressive disease (PD) = 6%
• There was higher overall response rate and depth of response in the IRd arm
  • ≥PR; IRd = 79% vs Rd = 73%
• Duration of response (DOR); IRd = 26 months vs Rd = 21.7 months
• Outcomes analysis based on time to best response; N = 548 pts
  • Time to best response: IRd = 2.9 months vs Rd = 2.8 months, p = > 0.05
  • Early responders: IRd = 61% vs Rd = 60%
  • Late responders: IRd = 39% vs Rd = 40%
• Pts with PR, late responders vs early responders: HR = 0.6 (95% CI, 0.26-1.39), p = 0.23
• Pts with ≥VGPR, late responders vs early responders: HR = 0.25 (95% CI, 0.09-0.7), p = <0.01

This subgroup analysis confirms population outcome findings of other TOURMALINE-MM1 trials.  It re-enforces the finding that late responders have better PFS and DOR, compared to early responders, and that deeper responses correlate to better PFS.  Clinicians are therefore cautioned not to change treatment plans too early when responses are not seen in the first four months; longer duration of treatment did not appear to affect the safety profile. The ability to look at outcomes in specific populations allows for patient tailored treatment plans and superior treatment outcomes for patients.