Pooled Real-World Data Support Earlier Line Use of IRd in Relapsed/Refractory Multiple Myeloma

A pooled analysis of the INSIGHT MM, UVEA-IXA, and REMIX observational studies found that real-world outcomes with ixazomib/lenalidomide/dexamethasone were consistent with those reported in the TOURMAILINE-MM1 study.

A pooled analysis of the INSIGHT MM (NCT02761187), the phase 2 UVEA-IXA (NCT03439293), and REMIX (NCT03433001) observational studies (INSURE) found that real-world outcomes with ixazomib (Ninlaro)/lenalidomide (Revlimid)/dexamethasone (IRd) were consistent with those reported in the phase 3 TOURMAILINE-MM1 study (NCT01564537), according to a poster presented during the 2022 Pan Pacific Lymphoma Conference.1

Specifically, investigators found that the median progression-free survival (PFS) and overall response rate (ORR) among real-life patients with relapsed or refractory multiple myeloma receiving treatment in routine clinical practice was 19.9 months (95% CI, 16.6-23.6) and 65%, respectively. These data correlated with the PFS and ORR findings reported in the TOURMALINE-MM1 trial, which were 20.6 months, and 78%, respectively. No new safety concerns were observed in this analysis.

INSURE pooled analysis encompassed 564 patients with a median overall time to next treatment (TTNT) in the real-world setting of 18.4 months overall (95% CI, 15.3-20.8). The TTNT was numerically longer in patients who received IRd in an earlier line setting: patients treated with the regimen as a second- or third-line treatment achieved a median TTNT of 20.7 (95% CI, 17.0-27.5) and 17.2 months (95% CI, 14.5-26.0), respectively, vs 12.8 months as a fourth-line or later treatment. When translated into PFS data, the median PFS in this population was also superior in the second- or third-line setting (21.7 [95% CI, 18.6-35.2] vs 19.7 months [95% CI, 13.9-26.3], respectively) vs 11.6 months (95% CI, 7.2-not estimable [NE]) in the fourth line.

Investigators reported data by frailty status in the findings. Among patients in the non-frail population (n = 242) with relapsed or refractory multiple myeloma, the median TTNT in the real-world setting was 21.4 months (95% CI, 16.1-27.5) and the median PFS was 21.6 months (95% CI 18.2-30.0). Among frail patients (n = 164), the median TTNT in the was 12.6 months (95% CI, 9.9-15.3) and the median PFS was 11.8 months (95% CI, 9.0-15.6).

“Our results suggest a greater benefit of treatment with IRd in earlier vs later lines, consistent with reports from previous, smaller real-world studies of IRd in patients [with relapsed or refractory multiple myeloma,” study authors wrote in the poster. “In addition, this analysis provides important insights on the effectiveness of IRd in frail patients, helping to increase understanding of achievable outcomes in this subpopulation.”

In 2015, findings from the TOURMALINE-MM1 study supported the FDA’s approval of IRd for patients with relapsed or refractory multiple myeloma. The trial demonstrated that the addition of ixazomib to Rd bested placebo plus Rd in improving PFS (20.6 months vs 14.7 months; HR, 0.74) and ORR (78% vs 72%, respectively), with limited added toxicity.

Oncology providers are aware that routine clinical practice data often differ from data reports for clinical trials in multiple myeloma. Study authors noted that this reality may be exacerbated by the fact that 72% of patients with relapsed or refractory multiple myeloma do not meet the eligibility criteria for randomized clinical trials and that real-world analyses with less stringent eligibility criteria may allow for a wider population of participants–thus providing more informative findings on the efficacy of an agent in routine clinical practice.

Multiple retrospective and prospective observation studies have compared the efficacy of IRd in later-line therapies to the efficacy observed in TOURMALINE-MM1. However, the INSURE study pooled data from 3 large observational studies to gain a comprehensive view of the comparisons between real-world and clinical trial agent implications. PFS and TTNT represented the trials’ key outcome measures, with DOT, OS, ORR, and safety as secondary outcomes.

Ultimately, 564 patients were included in INSURE, with a median number of therapy lines of 2 (range, 1-12) Most patients received IRd in the second-line (40.8%) or the third-line (38.1%). The median time from diagnosis to treatment with IRd was 39.3 months overall, and 29.7, 43.4, and 71.1 months for patients being treated in the second-, third-, and fourth-line or further setting, respectively.

With a median duration of follow-up time of 18.5 months across all patients receiving IRd, the median duration of treatment (DOT) was 14.0 months overall. This DOT was numerically longer among patients who received IRd in the second- or third-line setting than in patients who received IRd as fourth-line or later therapy (16.9 and 14.8 months vs 7.5 months, respectively). DOT was also numerically longer in the non-frail population than among the frail population (16.1 months vs 9.7 months).

Overall survival data were not yet mature, in neither the overall or specified later line settings, except for in the third-line: 39.4 months (95% CI, 27.2- NE). Median OS was not reached in non-frail patients, although in the frail population it was 20.1 months (95% CI, 17.5-30.4). A total 184 of patients (32.6%) died while on study.

Among patients who received IRd as second-, third-, or fourth-line therapy, the ORR was 70%, 63%, and 53%, respectively. Notably, there was a higher proportion of non-frail (42%) patients who achieved a very good or great partial response compared with frail patients (17%).

Because of inconsistencies in original reporting, INSURE investigators listed safety separately per original clinical trial. However, in INSIGHT MM (n = 181) and UVEWA-IXA (n = 195), the number of patients who required dose reductions in ixazomib because of adverse events (AEs) was 26 vs 18, respectively. The number of patients who needed to discontinue ixazomib because of AEs was 54 and 33, respectively. In the REMIX study (n = 188), the percentage of AEs was 64.9%, 37.8% of which were defined as serious. The most common serious AEs were plasma cell myeloma (5.3%) and thrombocytopenia (5.3%).

Study authors noted that the inherent difficulties in real-world studies, including selection and confounding biases, missing data, and inconsistent data reporting across study sites, potentially limit the findings. Furthermore, although the analysis provides perspective on the drug’s utility in a frailer population, “future analyses should focus on further evaluation of the effectiveness of therapies in frail and non-frail MM patients in the real world,” they concluded.


Zonder JA, Leleu X, Macro M, et al. INSURE: a global pooled analysis (INSIGHT MM, UVEA-IXA, and REMIX) of patients (pts) with relapsed/refractory multiple myeloma ixazomib-lenalidomide-dexamethasone (IRd) in routine clinical practice.Presented at: 2022 Pan Pacific Lymphoma Conference: July 18-22, 2022; Koloa, Hawaii.