Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Standard of Care in Latin America for Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Propensity Score Matching Analysis

The addition of novel agents such as daratumumab to regimens such as VMP and Rd has been shown to be effective and well tolerated in randomized clinical trials of transplant-ineligible patients with NDMM [4‐6]. Accordingly, such treatment strategies are becoming more common in many countries; however, this practice has yet to be widely adopted in Latin America, where SoC regimens rely on bortezomib and thalidomide. In the absence of a head-to-head comparison of D-VMP with the SoC regimens used in Latin America, a PSM analysis was conducted to estimate the relative effectiveness of these treatments. This methodology adjusted for baseline imbalances that might affect outcomes and treatment assignments; this reduces the impact of confounding and strengthens the validity of findings [15, 16]. In this PSM analysis, D-VMP showed superior effectiveness compared with bortezomib- and thalidomide-based regimens that are commonly used as SoC in Latin America in transplant-ineligible patients with NDMM. In a naïve comparison and propensity score matched analyses of the VMP arm of ALCYONE and the SoC group of HOLA, there were no statistically significant differences in PFS (data not shown), indicating that the improvements in effectiveness are due to the addition of daratumumab to VMP.

Several challenges have been identified for the management of patients with MM in Latin America. In an internet-based questionnaire of regional MM reference centers [7] and a subsequent survey of hematologists from 15 Latin American countries [8], variation in access to diagnostic tests and treatments in public versus private centers was reported. Similar to the findings of the HOLA study [9], bortezomib- and thalidomide-based regimens were reported as common first-line treatment options for transplant-ineligible patients with NDMM [7, 8]. As of 2018, daratumumab had been approved for MM in eight Latin American countries (in four countries for relapsed refractory MM only); however, access is limited because of reimbursement and local policies [8, 17]. Of note, patients with MM who were treated at public centers in Mexico were more likely to be diagnosed with advanced-stage disease and have poorer outcomes than those treated at private centers [18]. Reduced disparity between public and private centers and increased access to new treatments are needed to improve patient care in this region. The results presented here support the adoption of daratumumab-containing regimens in Latin America.

There were key differences between the ALCYONE and HOLA populations that resulted in marked reductions in matched sample sizes compared with the initial cohorts. The proportion of patients who were aged 65 years or more was 90% in the D-VMP arm of ALCYONE [4] but only 51% in the cohort of patients who did not receive ASCT in HOLA [9]. Patients evaluated in the HOLA study may not have received ASCT because of underlying medical issues (60% had at least one selected comorbidity documented [9]) and/or because of inconsistent access to ASCT in different Latin American countries [7, 8], rather than because of age.

Analyses based on propensity scores do have some limitations that must be considered when interpreting these findings. In this example, the performance of PSM was not optimal. Regression on matched pairs was conducted to address imbalance on the matching variables. In addition, residual confounding is possible for cross-study comparisons, especially when comparing randomized clinical trials with real-world study results. Patient management, treatment compliance, response assessment, response criteria, and loss to follow-up may differ between these two settings. Patients in randomized clinical trials are more homogenous and receive better SoC than in the real-world setting; since real-world data for D-VMP are lacking, the performance of this regimen in the clinical trial versus real-world setting cannot be equalized. In this analysis, matching was limited by the availability and quality of the data available for patients from the HOLA study (age, sex, ISS stage, chronic kidney disease, and hypercalcemia), which may result in information bias. Other prognostic factors, including Eastern Cooperative Oncology Group performance status, myeloma type, and cytogenetic risk could not be adjusted for, as these were not consistently available in the HOLA registry. Additionally, there is the potential for selection bias, as patients from the HOLA study represented a sample specifically selected for Latin America and less than 2% of the patients in the ALCYONE study were from Latin America. Finally, some imbalances in baseline characteristics persisted after matching. Although these imbalances were not significant, it is possible that they introduced bias in the indirect comparison.

In addition to limitations related to the PSM methodology, it should be noted that the HOLA study, which evaluated patients diagnosed with MM between 2008 and 2015, may not be fully representative of current treatment patterns in Latin America, although it is the most recent data set available for this population. Nevertheless, the HOLA study was considered a valid source for this analysis given the large sample size and the acquisition of data for patient characteristics, treatments, and effectiveness outcomes.