Risk Groups in Relapsed and Refractory Multiple Myeloma Treated By Lenalidomide Based Triplets - Analysis of the Czech Myeloma Group

Aims: This study aims to present real-world outcomes of lenalidomide-based triplets with daratumumab (DRD), carfilzomib (KRD), and ixazomib (IRD) in patients with relapsed and/or refractory multiple myeloma (RRMM). It also examines the impact of risk features on prognosis, taking into account the population's heterogeneity. Patients and Methods: Our cohort included 538 RRMM patients treated within 1st-3rd relapse. The patients were divided into three groups: DRD cohort (N = 224), KRD cohort (N = 143), and IRD cohort. The IRD cohort was further subdivided based on treatment timing: early IRD (E-IRD, N = 104), patients treated within a Named Patient Program with no competitive RD triplet or clinical trial, and late IRD (L-IRD, N = 67), predominantly including patients generally ineligible for KRD or DRD regimens. Patients from clinical trials and those with follow-ups shorter than six months were excluded. We performed Matching-Adjusted Indirect Comparison (MAIC) to account for differences between patient cohorts, such as age (median 65.5 vs. 64.4 vs. 67.2 vs. 69.9 years), performance status (PS 0 or 1 in 87.9% vs. 92.2% vs. 83.5% vs. 76.1%), pretreatment (1 previous line in 73.2% vs. 70.6% vs. 62.5% vs. 38.8%), lenalidomide pretreatment (8.5% vs. 8.4% vs. 6.7% vs. 28.4%), ISS stage (ISS 1 in 48.4% vs. 55.5% vs. 42.2% vs. 37.5%), presence of extraosseous disease (32.5% vs. 45.6% vs. 35.0% vs. 31.6%), and the presence of high-risk cytogenetics (24.6% vs. 42.7% vs. 32.3% vs. 53.1%). Risk groups included the presence of cytogenetic abnormalities (del17p13, t(4;14), t(14;16), gain/amp1q21), International Staging System (ISS) and Durie-Salmon (DS) groups, refractoriness status (i.e., relapsed vs. relapsed and refractory vs. primary refractory disease), and the presence of extraosseous disease. Results: The outcomes of the unmatched population were presented earlier and showed median progression-free survival (mPFS) for DRD, KRD, E-IRD, and L-IRD as 23.64, 16.52, 19.97, and 11.57 months, respectively (p < 0.001). After matching for age, line of treatment, ISS stage, and pretreatment by lenalidomide or IMiDs, DRD remained the most effective regimen (mPFS 17.38-23.63 months), except when matching for high-risk cytogenetics, which slightly favored proteasome inhibitors over daratumumab, though the differences were insignificant. High-risk features negatively impacted PFS in most pre-specified groups: del17p13 in DRD (mPFS 5.87 vs. 20.69 months, p < 0.001), non-significant in KRD and IRD; t(4;14) in DRD (mPFS 9.05 vs. 21.57 months, p < 0.001), in KRD (mPFS 12.62 vs. 17.90 months, p = 0.03), non-significant in IRD; gain/amp1q21 in DRD (mPFS 11.87 vs. 36.3 months, p = 0.002), in KRD (mPFS 12.62 vs. 23.54 months, p = 0.01), and in E-IRD (mPFS 13.25 vs. 30.07 months, p = 0.003). Low patient counts in t(14;16) precluded valid statistics. Similar results were observed in patients with extraosseous disease: DRD (mPFS NA vs. 36.3 months, p = 0.038), KRD (mPFS 5.15 vs. 23.41 months, p < 0.001), and E-IRD (mPFS 8.66 vs. 29.67 months, p = 0.002). Conclusions: The MAIC analysis confirmed better outcomes with DRD compared to other lenalidomide-based triplets in RRMM, except in patients with high-risk cytogenetics. Outcomes for patients with adverse cytogenetics were better with proteasome inhibitors than daratumumab, though differences were not significant. The presence of gain/amp1q21 or extraosseous disease were significant negative prognostic factors across all cohorts. Patients without gain/amp1q21 or extraosseous disease achieved significantly longer mPFS, comparable to outcomes reported in clinical trials. Supported by MH CZ - DRO (FNOl, 00098892).