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Comparable outcomes with ixazomib-lenalidomide-dexamethasone in routine clinical practice compared to the phase III TOURMALINE-MM1 trial

Pooled data from 2 large multiple myeloma (MM) registries (Czech RMG and INSIGHT MM) indicate that the effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) in routine clinical practice is comparable to what was reported in the pivotal TOURMALINE-MM1 trial. The analysis of these real-world data also indicate that patients receiving IRd in earlier treatment lines of relapse have better outcomes than patients receiving it after multiple relapses. Furthermore, exploratory data indicate that the outcome for patients receiving IRd at the time of biochemical relapse is better than when patients receiving it when they experience a symptomatic/clinical relapse. Finally, receiving a lenalidomide-based regimen immediately prior to IRd did not seem to negatively impact the response rate, or the depth and duration of the responses to IRd.

Background

Based on the results of the phase III TOURMALINE-MM1 study, the IRd combination was approved for the treatment of patients with relapsed/refractory (RR) MM who received ≥1 prior line of therapy. In this study, IRd was found to be associated with a median progression-free survival (PFS) of 20.6 months and an overall response rate of 78%, which was significantly better than the 14.7 months median PFS and 72% ORR rate seen with Rd alone. However, it is well known that efficacy and safety results obtained in the well-controlled setting of a randomized trial often differ from what is seen in routine clinical practice. In fact, a large proportion of MM patients seen in routine practice do not meet the standard eligibility criteria for randomized controlled trials (RCT), which contributes to the gap observed between outcomes reported in RCTs and in routine clinical practice in the real world. Data from real-world studies can help to fill in this gap as they have less stringent eligibility criteria and include a more diverse patient population. In an attempt to assess whether IRd performs equally well in clinical practice as it did in TOURMALINE-MM1, Hájek et al. pooled the data from two large MM registries: the global INSIGHT MM study including over 4,300 adult patients with MM and the Czech Registry of Monoclonal Gammopathies (RMG) which comprises data of more than 6,000 patients.

Results

Overall, 217 patients (83 in INSIGHT MM and 134 from RMG) were included in this analysis. Patients had received a median of 2 prior treatment lines with approximately 80% of patients receiving IRd in second (43%), or third line (35%). The median age of the included patients was 67 years, with 12% of patients being older than 75 years. In total, 85% of patients had an ECOG performance status (PS) of 0-1, 62% had clinical progression at the start of IRd therapy, while the remaining 38% had biochemical progression only.

The median follow-up for all patients in the analysis was 12.6 months, while the median time from diagnosis to the start of IRd was 42.1 months. In total, 37 INSIGHT MM patients and 115 RMG patients were evaluable for response. In INSIGHT MM, the ORR was reported at 76% (with 14% and 22% of patients obtaining a complete [CR], or a very good partial response [VGPR], respectively), while the ORR to IRd among RMG patients was 74% (12% CR, 24% VGPR). Overall, the median duration of response (DoR) in this analysis was 11.9 months, with a median time to next treatment (TTNT) of 31.5 months and a median progression-free survival (PFS) of 21.6 months. Patients who received IRd in second or third line had a longer median DoR than patients receiving it in fourth or further line (14.3 and 16.5 months vs. 7.7 and 5.6 months, respectively). Similarly, also the TTNT was longer for patients receiving IRd in earlier vs. later lines (median TTNT: 35.9, 26.2, 16.5 and 20.7 months for IRd in 2nd, 3rd, 4th and further line, respectively) and this was also the case for PFS (median PFS: 30.2, 23.2, 14.1 and 6.7 months for IRd in 2nd, 3rd, 4th and further line, respectively). At the time of the data cut-off, 53 patients had died resulting in a median OS of 36.7 months.

In an exploratory analysis investigators also looked at the outcome of patients on IRd in function of the type of relapse. In this exploratory analysis, patients who received IRd at the time of a biochemical relapse were found to have a numerically longer DoR, TTNT, PFS and OS compared to patients who initiated IRd at the time of clinical relapse. Finally, a second exploratory analysis suggested that receiving a lenalidomide-based regimen immediately prior to IRd did not appear to negatively impact the ORR, the depth of response, or the DoR.

Ixazomib and lenalidomide dose reductions were required in 16% and 36% of patients, respectively. Of them, 10% (21/217) and 21% (46/217) required a dose reductions due to adverse events. Ixazomib and lenalidomide discontinuations were reported in 44% and 45% of patients, respectively (32% and 31% due to adverse events).

Conclusions

The pooled analysis of two real-world studies indicate that IRd exhibits similar efficacy in real-life practice as it did in the pivotal phase III TOURMALIME-MM1 trial (median PFS: 21.6 and 20.6 months, respectively; ORR: 74% and 78%, respectively). Patients who received IRd in earlier treatment lines were found to have a longer DoT, TTNT and PFS compared to patients who received IRd in fourth line or beyond. Furthermore, exploratory analyses indicate that patients receiving IRd at the time of a biochemical relapse have better outcomes than patients receiving it when CRAB criteria were observed or when extramedullary disease was seen (clinical relapse). In addition, receiving IRd immediately after a lenalidomide-based regimen did not seem to impact the rate, quality or durability of the response to IRd. Finally, IRd was well tolerated with no new safety signals, and low rates of dose reductions, or discontinuations due to adverse events.

Reference

Hájek R, Minarik J, Straub J, et al. Closing the efficacy and effectiveness gap: outcomes in relapsed/refractory multiple myeloma (RRMM) patients (pts) treated with ixazomib-lenalidomide-dexamethasone (IRd) in routine clinical practice remain comparable to the outcomes reported in the phase 3 Tourmaline-MM1 study. Presented at ASH 2019; Abstract 1845.

Speaker Roman Hájek

Hajek1

Roman Hájek, MD, University Hospital Ostrava, Ostrava, Czech Republic

 

See: Keyslides

 

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