The prognostic value of minimal residual disease (MRD) for progression-free survival (PFS) and overall survival (OS) was evaluated in a large cohort of patients with multiple myeloma (MM) using a systematic literature review and meta-analysis. Medline and EMBASE databases were searched for articles published up to 8 June 2019, with no date limit on the indexed database. Clinical end points stratified by MRD status (positive or negative) were extracted, including hazard ratios (HRs) on PFS and OS, P values, and confidence intervals (CIs). HRs were estimated based on reconstructed patient-level data from published Kaplan-Meier curves. Forty-four eligible studies with PFS data from 8098 patients, and 23 studies with OS data from 4297 patients were identified to assess the association between MRD status and survival outcomes. Compared with MRD positivity, achieving MRD negativity improved PFS (HR, 0.33; 95% CI, 0.29-0.37; P < .001) and OS (HR, 0.45; 95% CI, 0.39-0.51; P < .001). MRD negativity was associated with significantly improved survival outcomes regardless of disease setting (newly diagnosed or relapsed/refractory MM), MRD sensitivity thresholds, cytogenetic risk, method of MRD assessment, depth of clinical response at the time of MRD measurement, and MRD assessment premaintenance and 12 months after start of maintenance therapy. The strong prognostic value of MRD negativity and its association with favorable outcomes in various disease and treatment settings sets the stage to adopt MRD as a treatment end point, including development of therapeutic strategies. This large meta-analysis confirms the utility of MRD as a relevant surrogate for PFS and OS in MM.

Objectives: To show how clinical trial data can be extrapolated using historical trial data-based a priori distributions. Methods: Extrapolations based on 30-month pivotal multiple myeloma trial data were compared with 75-month data from the same trial. The 30-month data represent a typical decision-making scenario where early results from a clinical trial are extrapolated. Mature historical trial data with the same comparator as in the pivotal trial were incorporated in 2 stages. First, the parametric distribution selection was based on the historical trial data. Second, the shape parameter estimate of the historical trial was used to define an informative a priori distribution for the shape of the 30-month pivotal trial data. The method was compared with standard approaches, fitting parametric distributions to the 30-month data with noninformative prior. The predicted survival of each method was compared with the observed survival (DAUC) in the 75-month trial data. Results: The Weibull had the best fit to the historical trial and the log-normal to the 30-month pivotal trial data. The DAUC of the Weibull with informative priors was considerably smaller compared with the standard Weibull. Also, the predicted median survival based on the Weibull with informative priors was more accurate (melphalan and prednisone [MP] 40 months, and bortezomib [V] combined with MP [VMP] 62 months) than based on the standard Weibull (MP 45 months and VMP 72 months) when compared with the observed median (MP 41.3 months and VMP 56.4 months). Conclusions: Extrapolation of clinical trial data is improved by using historical trial data-based informative a priori distributions.

Introduction This study investigates the gender distribution in patients diagnosed with wild-type transthyretin amyloidosis cardiomyopathy (ATTRwt). Methods A systematic review and meta-analysis of the male proportion in diagnosed ATTRwt patients were conducted. To avoid overlapping population, pooled estimates in the primary analysis were based on all unique studies. In secondary analyses, we considered predefined subsets of studies based on study sample size, recruitment years, geography, study design, age at diagnosis, and method of diagnosis. Additional meta-regression analyses were tested for potential determinants of gender distribution. Results Twenty-eight unique studies (2542 patients) were included in the meta-analysis. Male proportion in patients with ATTRwt was 86.9% (95% confidence interval 81.5–91.6%). Studies, including patients older than 80 years at diagnosis, had a 29.1% ( p value < 0.001) lower male proportion compared to studies, including younger patients. After adjusting for age, studies using autopsy as a method of diagnosis had a 21.1% ( p value 0.002) lower male proportion compared to other studies. Conclusions Studies conducted to date suggest ATTRwt disproportionally affects males. The proportion of males was significantly impacted by the age at diagnosis and method diagnosis, which may suggest important gender-based differences in the clinical manifestation and diagnostic challenges of ATTRwt in females that warrant future research. Electronic supplementary material The online version of this article (10.1007/s40119-020-00205-3) contains supplementary material, which is available to authorized users.

No abstract

Aim: To compare daratumumab plus standard-of-care (SoC; bortezomib/thalidomide/dexamethasone [VTd]) and VTd alone with other SoC for transplant-eligible newly diagnosed multiple myeloma. Patients & methods: We conducted an unanchored matching-adjusted indirect comparison of progression-free and overall survival (PFS/OS) with D-VTd/VTd versus bortezomib/lenalidomide/dexamethasone (VRd), bortezomib/cyclophosphamide/dexamethasone (VCd) and bortezomib/dexamethasone (Vd). Results: After matching adjustment, significant improvements in PFS were estimated for D-VTd versus VRd (hazard ratio [HR]: 0.47 [95% CI: 0.33–0.69]), VCd (HR: 0.35 [95% CI: 0.21–0.58]) and Vd (HR: 0.42 [95% CI: 0.28–0.63]). OS was significantly longer with D-VTd versus VRd (HR: 0.31 [95% CI: 0.16–0.57]), VCd (HR: 0.35 [95% CI: 0.14–0.86]) and Vd (HR: 0.38 [95% CI: 0.18–0.77]). No significant PFS/OS differences were seen for VTd versus other SoC. Conclusion: This analysis supports front-line daratumumab for transplant-eligible newly diagnosed multiple myeloma.