Ixazomib, Lenalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma in Routine Clinical Practice: Extended Follow-Up Analysis and the Results of Subsequent Therapy

Abstract

Background: We confirmed the benefit of addition of ixazomib to lenalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM) in unselected real-world population. We report the final analysis for overall survival (OS), second progression free survival (PFS-2), and the subanalysis of the outcomes in lenalidomide (LEN) pretreated and LEN refractory patients. Methods: We assessed 344 patients with RRMM, treated with IRD (N = 127) or RD (N = 217). The data were acquired from the Czech Registry of Monoclonal Gammopathies (RMG). With prolonged follow-up (median 28.5 months), we determined the new primary endpoints OS, PFS and PFS-2. Secondary endpoints included the next therapeutic approach and the survival measures in LEN pretreated and LEN refractory patients. Results: The final overall response rate (ORR) was 73.0% in the IRD cohort and 66.8% in the RD cohort. The difference in patients reaching ≥VGPR remained significant (38.1% vs. 26.3%, p = 0.028). Median PFS maintained significant improvement in the IRD cohort (17.5 vs. 12.5 months, p = 0.013) with better outcomes in patients with 1–3 prior relapses (22.3 vs. 12.7 months p = 0.003). In the whole cohort, median OS was for IRD vs. RD patients 40.9 vs. 27.1 months (p = 0.001), with further improvement within relapse 1-3 (51.7 vs. 27.8 months, p ˂ 0.001). The median PFS of LEN pretreated (N = 22) vs. LEN naive (N = 105) patients treated by IRD was 8.7 vs. 23.1 months (p = 0.001), and median OS was 13.2 vs. 51.7 months (p = 0.030). Most patients in both arms progressed and received further myeloma-specific therapy (63.0% in the IRD group and 53.9% in the RD group). Majority of patients received pomalidomide-based therapy or bortezomib based therapy. Significantly more patients with previous IRD vs. RD received subsequent monoclonal antibodies (daratumumab—16.3% vs. 4.3%, p = 0.0054; isatuximab 5.0% vs. 0.0%, p = 0.026) and carfilzomib (12.5 vs. 1.7%, p = 0.004). The median PFS-2 (progression free survival from the start of IRD/RD therapy until the second disease progression or death) was significantly longer in the IRD cohort (29.8 vs. 21.6 months, p = 0.016). There were no additional safety concerns in the extended follow-up. Conclusions: The IRD regimen is well tolerated, easy to administer, and with very good therapeutic outcomes. The survival measures in unsorted real-world population are comparable to the outcomes of the clinical trial. As expected, patients with LEN reatment have poorer outcomes than those who are LEN-naive. The PFS benefit of IRD vs. RD translated into significantly better PFS-2 and OS, but the outcomes must be accounted for imbalances in pretreatment group characteristics (especially younger age and stem cell transplant pretreatment), and in subsequent therapies.

Efficacy and safety of daratumumab with ixazomib and dexamethasone in lenalidomide‐exposed patients after one prior line of therapy: Final results of the phase 2 study DARIA

“…However, a significant OS benefit was not observed in the final analysis, possibly due to the type of subsequent lines of therapies including an inferior proportion of patients in the IRd group who received daratumumab‐based compared with the Rd group 43 . Real‐world studies have confirmed the effectiveness and safety of IRd in the routine clinical practice in accordance with the clinical trial results 44–47 . Interestingly, pharmacoeconomic analyses both in the United States of America and in Europe have suggested that all‐oral IRd regimen is among the least expensive approved triplet regimens for patients with RRMM 48,49 …”

“…43 Real-world studies have confirmed the effectiveness and safety of IRd in the routine clinical practice in accordance with the clinical trial results. [44][45][46][47] Interestingly, pharmacoeconomic analyses both in the United States of America and in Europe have suggested that all-oral IRd regimen is among the least expensive approved triplet regimens for patients with RRMM. 48,49 The combination of Dara-Ixa-dex has been also evaluated in the first-line treatment of patients with NDMM who are not fit for ASCT.…”

A real‐world retrospective–prospective analysis of efficacy and safety of combined ixazomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma: The northern Italy experience

“…In the routine clinical practice, the all‐oral route of administration and the favorable safety profile make this regimen potentially suitable for the treatment of elderly pts with comorbidities and/or impaired PS 5,6 . Several observational studies have indeed reported a higher prevalence of older age, impaired PS, advanced stage disease, >2 pLoT in the real‐world population treated with IRd, showing comparable effectiveness with OR rates ranging from 60% to 74% and mPFS ranging from 11.4 to 43 m 7–15 . Moreover, a significant proportion of pts (17%–39%) in the real‐world setting has previous exposure to Len compared to only 12% in the MM1 study.…”

“…In the routine clinical practice, the all-oral route of administration and the favorable safety profile make this regimen potentially suitable for the treatment of elderly, frail patients (pts) [2][3][4] who are under-represented in the clinical studies. 5,6 Several observational studies [7][8][9][10][11][12][13][14][15] of IRd have confirmed the effectiveness of IRd with ORR ranging from 60% to 74% and mPFS from 11.4 to 27.6 m in real-world setting, despite a higher prevalence of elderly and heavily pre-treated pts, compromised performance status (PS), and advanced stage disease. A proportion of pts ranging from 17% to 38% in the published real-world studies had previous exposure to lenalidomide (Len) compared with only 12% in the MM1 study.…”

Impact of prior lenalidomide or proteasome inhibitor exposure on the effectiveness of ixazomib–lenalidomide–dexamethasone for relapsed/refractory multiple myeloma: A pooled analysis from the INSURE study

“…7 Furthermore, these findings are consistent with those reported in other real-world observational studies of IRd in patients with RRMM. 6,[8][9][10][11][12][13] Lenalidomide-containing regimens and proteasome inhibitors (PIs) are used commonly across lines of therapy (LoTs) for the treatment of patients with MM. 14 Although data on effectiveness outcomes following retreatment with agents used in earlier LoTs are limited, there is some evidence to suggest that patients may derive benefit from retreatment with an agent they have been previously exposed to (but are not refractory to).…”