Despite significant advancements in therapy of multiple myeloma (MM) over the past 20 years, most patients experience relapse, necessitating new treatment approaches. This study aims to compare the real-world effectiveness of lenalidomide (LEN)-based triplet therapies, specifically daratumumab (DRD), carfilzomib (KRD), and ixazomib (IRD), in relapsed/refractory multiple myeloma (RRMM).A retrospective registry-based study analyzed 538 RRMM patients undergoing therapy for their first to third relapse. The primary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), with a matching-adjusted indirect comparisons (MAIC) employed to address cohort differences.ORR was highest for DRD at 91.4%, followed by KRD (89.6%) and IRD cohorts (Early-IRD: 79.6%, Late-IRD: 70.8%). Median PFS for DRD was greater at 23.64 months compared to KRD (16.52 months) and IRD groups (Early-IRD: 19.97 months, Late-IRD: 11.57 months). The MAIC confirmed better outcomes for the DRD regimen. High-risk features were not overcome by any of the LEN-based regimens.The findings underscore the superior efficacy of DRD in achieving sustained responses in RRMM patients. The composition of the cohort is a crucial factor, extending beyond selection criteria. This study highlights the importance of real-world evidence in assessing treatment modalities in clinical settings.

• Keywords
• Lenalidomide triplets, Multiple myeloma, Relapsed/refractory, Risk groups,
• MeSH
• Drug Resistance, Neoplasm MeSH
• Adult MeSH
• Glycine analogs & derivatives   administration & dosage   MeSH
• Lenalidomide * administration & dosage   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * drug therapy   MeSH
• Multiple Myeloma * drug therapy   mortality   pathology   MeSH
• Antibodies, Monoclonal administration & dosage   therapeutic use   MeSH
• Oligopeptides administration & dosage   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Registries MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Boron Compounds administration & dosage   therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic epidemiology   MeSH
• Names of Substances
• carfilzomib MeSH Browser
• daratumumab MeSH Browser
• Glycine MeSH
• ixazomib MeSH Browser
• Lenalidomide * MeSH
• Antibodies, Monoclonal MeSH
• Oligopeptides MeSH
• Boron Compounds MeSH

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.

• Keywords
• immunomodulatory drugs, multiple myeloma, proteasome inhibitors, real-world analysis, relapsed and refractory,
• Publication type
• Journal Article MeSH

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum's deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.

• Keywords
• Bortezomib, Carfilzomib, Daratumumab, Ixazomib, Lenalidomide, Pomalidomide, Proteasome inhibitor triplet therapy, Real-world, Relapsed refractory multiple myeloma,
• MeSH
• Bortezomib therapeutic use   MeSH
• Glycine analogs & derivatives   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   MeSH
• Multiple Myeloma drug therapy   MeSH
• Antibodies, Monoclonal therapeutic use   MeSH
• Oligopeptides therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Boron Compounds therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Bortezomib MeSH
• carfilzomib MeSH Browser
• daratumumab MeSH Browser
• Glycine MeSH
• ixazomib MeSH Browser
• Antibodies, Monoclonal MeSH
• Oligopeptides MeSH
• Boron Compounds MeSH

Treatment options in multiple myeloma (MM) are increasing with the introduction of complex multi-novel-agent-based regimens investigated in randomized clinical trials. However, application in the real-world setting, including feasibility of and adherence to these regimens, may be limited due to varying patient-, treatment-, and disease-related factors. Furthermore, approximately 40% of real-world MM patients do not meet the criteria for phase 3 studies on which approvals are based, resulting in a lack of representative phase 3 data for these patients. Therefore, treatment decisions must be tailored based on additional considerations beyond clinical trial efficacy and safety, such as treatment feasibility (including frequency of clinic/hospital attendance), tolerability, effects on quality of life (QoL), and impact of comorbidities. There are multiple factors of importance to real-world MM patients, including disease symptoms, treatment burden and toxicities, ability to participate in daily activities, financial burden, access to treatment and treatment centers, and convenience of treatment. All of these factors are drivers of QoL and treatment satisfaction/compliance. Importantly, given the heterogeneity of MM, individual patients may have different perspectives regarding the most relevant considerations and goals of their treatment. Patient perspectives/goals may also change as they move through their treatment course. Thus, the 'efficacy' of treatment means different things to different patients, and treatment decision-making in the context of personalized medicine must be guided by an individual's composite definition of what constitutes the best treatment choice. This review summarizes the various factors of importance and practical issues that must be considered when determining real-world treatment choices. It assesses the current instruments, methodologies, and recent initiatives for analyzing the MM patient experience. Finally, it suggests options for enhancing data collection on patients and treatments to provide a more holistic definition of the effectiveness of a regimen in the real-world setting.

• MeSH
• Clinical Trials, Phase III as Topic MeSH
• Quality of Life MeSH
• Humans MeSH
• Disease Management MeSH
• Multiple Myeloma * drug therapy   MeSH
• Antineoplastic Agents * adverse effects   therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Antineoplastic Agents * MeSH