Ixazomib-Lenalidomide-Dexamethasone in Routine Clinical Practice: Effectiveness in Relapsed/refractory Multiple Myeloma

Hájek, Roman; Minařík, Jiří; Štraub, Jan; Pour, Luděk; Jungová, Alexandra; Berdeja, Jesús G.; Boccadoro, Mario; Brožová, Lucie; Spencer, Andrew; Rhee, Frits van; Vela‐Ojeda, Jorge; Thompson, Michael A.; Abonour, Rafat; Chari, Ajai; Cook, Gordon; Costello, Caitlin; Davies, Faith E.; Hungria, Vânia; Lee, Hans C.; Leleu, Xavier; Puig, Noemí; Rifkin, Robert M.; Terpos, Evangelos; Usmani, Saad Z.; Weisel, Katja; Zonder, Jeffrey A.; Bařinová, Magda; Kuhn, Matyáš; Silar, J; Čápková, Lenka; Gálvez, Kenny; Lu, Jin; Elliott, Jennifer; Stull, Dawn Marie; Ren, Kaili; Maisnar, Vladimír

doi:10.2217/fon-2020-1225

Cited by 14 publications

(13 citation statements)

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“…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 …”

Section: Discussionmentioning

confidence: 88%

“…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.…”

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confidence: 99%

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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

Terpos,

Ntanasis‐Stathopoulos,

Gavriatopoulou

et al. 2024

American J Hematol

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The use of lenalidomide in frontline therapy for patients with newly diagnosed multiple myeloma (MM) has increased the number of those who become refractory to lenalidomide at second line. In this context, we assessed the efficacy of daratumumab in combination with ixazomib and dexamethasone (Dara‐Ixa‐dex) in the prospective phase 2 study DARIA. Eligible patients had relapsed/refractory MM (RRMM) after one prior line with a lenalidomide‐based regimen. The primary endpoint was overall response rate (ORR). Secondary endpoints included survival outcomes, safety and changes in biomarkers of bone metabolism. Overall, 50 patients were enrolled (median age 69 years, 56% males). 32 (64%) patients were refractory to lenalidomide, and 17 (34%) had undergone autologous transplant. The ORR was 64% (n = 32); whereas 17 (34%) had a very good partial response or better. The median time to first response was 1.0 month. After a median follow‐up of 23.4 months, the median PFS and OS were 8.1 and 39.2 months, respectively. Furthermore, significant changes in markers of bone metabolism became evident as early as at 6 months on treatment. Regarding safety, 21 (42%) patients had ≥1 grade 3/4 adverse event (AE); the most common was thrombocytopenia (n = 9, 18%). 14 (28%) patients had ≥1 serious AE (SAE), the most common being acute kidney injury and pneumonia (n = 2, each). Four patients died due to infections. In conclusion, second‐line treatment with Dara‐Ixa‐dex in patients with RRMM pre‐treated with a lenalidomide‐based regimen resulted in rapid responses along with a favorable effect on bone metabolism.

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Section: Discussionmentioning

confidence: 88%

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confidence: 99%

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

Terpos,

Ntanasis‐Stathopoulos,

Gavriatopoulou

et al. 2024

American J Hematol

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Furlan,

Cea,

Pavan

et al. 2024

Cancer Medicine

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IntroductionIxazomib, lenalidomide, and dexamethasone (IRd) have been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) based on the results of the TOURMALINE‐MM1.Objectives and MethodsWe conducted a retrospective–prospective analysis of 106 RRMM patients (pts) treated with IRd in 21 centers in Northern Italy, with the aim to evaluate the efficacy and safety of IRd in real life.ResultsAt IRd initiation, 34% of pts were aged ≥75 (median 72.5), 8.5% had an ECOG performance status ≥2, 54.7% of evaluable pts carried high‐risk cytogenetic abnormalities [del17p and/or t(4;14) and/or t(14;16) and/or 1 g gain/amp], 60.2% had received ≥2 prior lines of therapy (pLoT), 57.5% were lenalidomide (Len)‐exposed (including both Len‐sensitive and Len‐refractory pts), and 22% were Len‐refractory. Main G ≥3 adverse events (AEs) were thrombocytopenia (16%) and neutropenia (12.3%). G ≥3 non‐hematologic AEs included infections (9.4%) and GI toxicity (diarrhea 5.7%, hepatotoxicity 2.8%), VTE, skin rash, and peripheral neuropathy were mainly G1‐2. The overall response rate was 56.4% (≥VGPR 30%). With a median follow‐up of 38 m, median PFS (mPFS) was 16 m and the 1‐year OS rate was 73%. By subgroup analysis, an extended PFS was observed for pts achieving ≥VGPR (mPFS 21.2 m), time from diagnosis to IRd ≥5 years (26.2 m), 1 pLoT (34.4 m), Len‐naïve (NR), age ≥70 (20 m). In pts exposed to Len, non‐refractory in any prior line and immediately prior to IRd, mPFS was 16 and 18 m, respectively. An inferior PFS was seen in Len‐refractory pts (4.6 m). By multivariate analysis, independent predictors of PFS were age ≥70 (HR 0.6), time from diagnosis ≥5 years (HR 0.32), refractoriness to Len in any prior line (HR 3.33), and immediately prior (HR 4.31).ConclusionIRd might be effective and safe in RRMM pts with an indolent disease, in early lines of treatment, and who proved Len‐sensitive, independent of age, and cytogenetic risk.

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“…Several RWE worldwide supported the benefit of ixazomib-based treatment in RRMM patients regarding PFS [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. None of these studies compared IRD vs. RD but the outcomes were quite similar with median PFS varying from 17–31 months.…”

Section: Discussionmentioning

confidence: 99%

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

Minařík

Radocha

Jungová

et al. 2022

Cancers

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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.

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Ixazomib-Lenalidomide-Dexamethasone in Routine Clinical Practice: Effectiveness in Relapsed/refractory Multiple Myeloma

Cited by 14 publications

References 35 publications

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

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

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

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

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