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Time-dependent endpoints as predictors of overall survival in multiple myeloma.

ABSTRACT: BACKGROUND: Supporting health care sector decisions using time-dependent endpoints (TDEs) such as time to progression (TTP), progression-free survival (PFS), and event-free survival (EFS) remains controversial. This study estimated the quantitative relationship between median TDE and median overall survival (OS) in multiple myeloma (MM) patients. METHODS: Studies (excluding allogeneic transplantation) published from 1970 to 2011 were systematically searched (PubMed). The nonparametric Spearman's rank correlation coefficient measured the association between median TDE and OS. The quantitative relationship between TDEs and OS was estimated with a two-step approach to a simultaneous Tobit model. RESULTS: We identified 153 studies: 230 treatment arms, 22,696 patients and mean study duration of 3.8 years. Mean of median TDEs was 22.5 months and median OS was 39.1 months. Correlation coefficients of median TTP, PFS, and EFS with median OS were 0.51 (P = 0.003), 0.75 (P < 0.0001), and 0.84 (P < 0.0001), respectively. We estimate a 2.5 month (95% confidence interval, 1.7-3.2) increase in median OS for each additional month reported for median TDEs. There was no evidence that this relationship differed by type of surrogate. CONCLUSION: TDEs predict OS in MM patients; this relationship may be valuable in clinical trial design, drug comparisons, and economic evaluation.

SUBMITTER: Felix J

PROVIDER: S-EPMC3607860 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Time-dependent endpoints as predictors of overall survival in multiple myeloma.

Félix Jorge J Aragão Filipa F Almeida João M JM Calado Frederico J FJ Ferreira Diana D Parreira António B S AB Rodrigues Ricardo R Rijo João F R JF

BMC cancer 20130316

<h4>Background</h4>Supporting health care sector decisions using time-dependent endpoints (TDEs) such as time to progression (TTP), progression-free survival (PFS), and event-free survival (EFS) remains controversial. This study estimated the quantitative relationship between median TDE and median overall survival (OS) in multiple myeloma (MM) patients.<h4>Methods</h4>Studies (excluding allogeneic transplantation) published from 1970 to 2011 were systematically searched (PubMed). The nonparametr ...[more]

PMID: 23497363

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Project description:Since the introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, more patients with multiple myeloma are achieving deep, durable responses and disease control, and are living longer. These improvements have afforded more robust analyses of the relationship between response and survival. Generally, these studies have demonstrated that improvements in the quality of response across all stages of treatment are associated with better disease control and longer survival. Thus, achievement of maximal response should be strongly considered, particularly in the frontline setting, but must also be balanced with tolerability, quality of life and patient preferences. In select patients, achievement of a lesser response may be adequate to prolong survival, and attempts to treat these patients to a deeper response may place them at unnecessary risk without significant benefit. Maintenance therapy has been shown to improve the quality of response and disease control and, in some studies, survival. Studies support maintenance therapy for high-risk patients as a standard of care, and there are emerging data supporting maintenance therapy in standard-risk patients to improve progression-free and possibly overall survival. Multidrug regimens combining a proteasome inhibitor and an IMiD have shown exceptional response outcomes with acceptable increases in toxicity in both the frontline and salvage settings, and are becoming a standard treatment approach. Moving forward, the use of immunophenotypic and molecular response criteria will be essential in better understanding the impact of highly active and continuous treatment regimens across myeloma patient populations. Future translational studies will help to develop antimyeloma agents to their fullest potential. The introduction of novel targeted therapies, including the IMiD pomalidomide and the proteasome inhibitors carfilzomib and ixazomib (MLN9708), will provide greater options to individualize treatment and help patients achieve a clinically meaningful response.

Project description:BackgroundSurrogate endpoints (SEs), such as progression-free survival (PFS) and objective response rate (ORR), are frequently used in clinical trials. The relationship between SEs and overall survival (OS) has not been well described in metastatic urothelial cancer (MUC).ObjectiveWe evaluated trial-level data to assess the relationship between SEs and OS. We hypothesize a moderate surrogacy relationship between both PFS and ORR with OS.Design setting and participantsWe systematically reviewed phase 2/3 trials in MUC with two or more treatment arms, and report PFS and/or ORR, and OS.Outcome measurements and statistical analysisLinear regression was performed, and the coefficient of determination (R2) and surrogate threshold effect (STE) estimate were determined between PFS/ORR and OS.Results and limitationsOf 3791 search results, 59 trials and 62 comparisons met the inclusion criteria. Of the 53 trials that reported PFS, 31 (58%) reported proportional hazard regression for PFS and OS. Linear regression across trials demonstrated an R2 of 0.60 between hazard ratio (HR) for PFS (HRPFS) and HR for OS (HROS), and an STE of 0.41. Linear regression of ΔPFS (median PFS in months of the treatment arm - that of the control arm) and ΔOS demonstrated an R2 of 0.12 and an STE of 14.1 mo. Thirty trials reported ORRs. Linear regression for ORRratio and HROS among all trials found an R2 of 0.08; an STE of 95% was not reached at any value and ΔORR and HROS similarly demonstrated a poor correlation with an R2 value of 0.03.ConclusionsPFS provides only a moderate level of surrogacy for OS; An HRPFS of ≤0.41 provides 95% confidence of OS improvement. ORR is weakly correlated with OS and should be de-emphasized in MUC clinical trials. When PFS is discussed, proportional hazard regression should be reported.Patient summaryWe examined the relationship between surrogate endpoints, common outcomes in clinical trials, with survival in urothelial cancer trials. Progression-free survival is moderately correlated, while objective response rate had a poor correlation with survival and should be de-emphasized as a primary endpoint.

Project description:Multiple myeloma (MM) is characterized by the malignant proliferation of monoclonal plasma cells in the bone marrow with an elevation in monoclonal paraprotein, renal impairment, hypercalcemia, lytic bony lesions, and anemia. Immune cells and associated cytokines play a significant role in MM growth, progression, and dissemination. While some cytokines and their clinical significance are well described in MM biology, others remain relatively unknown. The present study examines the influence on progression-free survival (PFS) and overall survival (OS) by the serum levels of 27 selected cytokines in 61 newly diagnosed MM patients receiving first-line therapy with bortezomib-based regimens. The measurements were performed using a Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay and a MAGPIX Multiplex Reader, based on the Bio-Plex® 200 System (Bio-Rad). The following levels were determined: IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF. Most patients received a VCD chemotherapy regimen (bortezomib, cyclophosphamide, and dexamethasone). In the final multivariate model, IL-13 cytokine level (HR 0.1411, 95% CI: 0.0240-0.8291, p = 0.0302) and ASCT (HR 0.3722, 95% CI: 0.1826-0.7585, p = 0.0065) significantly impacted PFS. Furthermore, ASCT (HR 0.142, 95% CI: 0.046-0.438, p = 0.0007), presence of bone disease at diagnosis (HR 3.826, 95% CI: 1.471-9.949, p = 0.0059), and two cytokine levels-IL-1Ra (HR 1.017, 95% CI: 1.004-1.030, p = 0.0091) and IL-4 (HR 0.161, 95% CI: 0.037-0.698, p = 0.0147)-were independent predictors of OS. Three clusters of MM patients were identified with different cytokine profiles. In conclusion, serum pretreatment levels of IL-13 and IL-4 are predictors of better PFS and OS, respectively, whereas IL-1Ra pretreatment levels negatively impact OS in MM patients treated with bortezomib-based chemotherapy. Cytokine signature profile may have a potential influence on the outcome of patients treated with bortezomib.

Project description:BackgroundAlkaline phosphatase (ALP) reflects changes in the condition of multiple myeloma (MM) patients to some extent. However, the relationship of ALP in MM remains uncertain. Our study aimed to determine the association between initial ALP levels and overall survival in newly diagnosed MM patients.MethodsClinical data from 202 newly diagnosed MM patients at Beijing Chaoyang Hospital between 2012 and 2016 were collected. Baseline characteristics, disease progression staging, serum markers, and patient survival data were recorded. The cut-off value for ALP was calculated based on patient survival data, and patients were divided into groups. Differences in patients' 3- and 5-year survival rates, liver function, bone disease and other indicators among different groups were compared. Independent risk factors influencing newly diagnosed MM patients were identified using COX regression analysis.ResultsPatients were categorized into three groups based on ALP cut-off points: Group 1 (ALP <70 U/L), Group 2 (ALP 70 to <120 U/L), and Group 3 (ALP ≥120 U/L). Significant differences were observed in lactate dehydrogenase, serum calcium, white blood cell count, hemoglobin, and liver function indicators (including alanine aminotransferase, aspartate aminotransferase, albumin, and γ-glutamyl transferase) among different ALP groups (P<0.05). ALP levels varied significantly among patients with different bone disease grades (P<0.05). Median survival times for Groups 1, 2, and 3 were 25, 52, and 31 months, respectively. Group 2 exhibited significantly higher 3-year survival compared to the other two groups (P=0.006), while no significant difference was observed in 5-year survival among the three groups (P=0.51). Age, International Staging System staging, aspartate aminotransferase, β2-microglobulin, ALP grading, and severe bone disease were identified as independent factors influencing survival in newly diagnosed patients (P<0.05).ConclusionsALP levels are correlated with the prognosis of MM patients, and an ALP range of 70 to <120 U/L reflects a better survival expectation.

Project description:Multiple myeloma promotes systemic skeletal bone disease that greatly contributes to patient morbidity. Resorption of type I collagen-rich bone matrix by activated osteoclasts results in the release of sequestered growth factors that can drive progression of the disease. Matrix metalloproteinase-13 (MMP13) is a collagenase expressed predominantly in the skeleton by mesenchymal stromal cells (MSC) and MSC-derived osteoblasts. Histochemical analysis of human multiple myeloma specimens also demonstrated that MMP13 largely localizes to the stromal compartment compared with CD138+ myeloma cells. In this study, we further identified that multiple myeloma induces MMP13 expression in bone stromal cells. Because of its ability to degrade type I collagen, we examined whether bone stromal-derived MMP13 contributed to myeloma progression. Multiple myeloma cells were inoculated into wild-type or MMP13-null mice. In independent in vivo studies, MMP13-null mice demonstrated significantly higher overall survival rates and lower levels of bone destruction compared with wild-type controls. Unexpectedly, no differences in type I collagen processing between the groups were observed. Ex vivo stromal coculture assays showed reduced formation and activity in MMP13-null osteoclasts. Analysis of soluble factors from wild-type and MMP13-null MSCs revealed decreased bioavailability of various osteoclastogenic factors including CXCL7. CXCL7 was identified as a novel MMP13 substrate and regulator of osteoclastogenesis. Underscoring the importance of host MMP13 catalytic activity in multiple myeloma progression, we demonstrate the in vivo efficacy of a novel and highly selective MMP13 inhibitor that provides a translational opportunity for the treatment of this incurable disease. SIGNIFICANCE: Genetic and pharmacologic approaches show that bone stromal-derived MMP13 catalytic activity is critical for osteoclastogenesis, bone destruction, and disease progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2415/F1.large.jpg.

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Time-dependent endpoints as predictors of overall survival in multiple myeloma.

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Time-dependent endpoints as predictors of overall survival in multiple myeloma.

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