— Meta-analysis found benefit in patients with high-risk cytogenetics regardless of backbone
Patients with newly diagnosed or relapsed/refractory multiple myeloma with high-risk cytogenetics derived a progression-free survival (PFS) benefit from the addition of daratumumab (Darzalex) to a variety of backbone regimens, according to the results of a meta-analysis.
The meta-analysis included data from six phase III trials comparing backbone multiple myeloma regimens with or without daratumumab in patients with high-risk cytogenetics defined as the presence of t(4;14), t(14;16), or del(17p). The addition of daratumumab resulted in improved PFS for patients with newly diagnosed disease (pooled HR 0.67, 95% CI 0.47-0.95, P=0.02) and those with relapsed or refractory disease (pooled HR 0.45, 95% CI 0.30-0.67, P<0.001), reported Smith Giri, MD, MHS, of the University of Alabama at Birmingham, and colleagues in JAMA Oncology.
The positive effect of daratumumab was not weakened by the three trials having different backbone regimens and different age groups, the researchers noted. The meta-analysis found little evidence of heterogeneity (Cochran Q; P=0.77; I2=0%).
For newly diagnosed disease, the analysis included data from the ALCYONE, MAIA, and CASSIOPEIA studies. In each individual study, the addition of daratumumab did not significantly improve PFS among patients with high-risk cytogenetics. In these studies, 15.9%, 14.3%, and 15.5% of patients had high-risk cytogenetics, respectively.
“It is possible that the benefit of daratumumab for high-risk multiple myeloma was not identified in those trials owing to relatively small sample sizes,” the researchers wrote. “The current meta-analysis combined multiple studies with similar design to increase the power to answer a scientifically and clinically relevant question.”
For relapsed/refractory disease, data from CASTOR, POLLUX, and CANDOR was included. In contrast to the trials of newly diagnosed disease, CASTOR and POLLUX both showed a benefit for daratumumab in terms of PFS among patients with high-risk cytogenetics; only CANDOR did not. Again, there was no significant heterogeneity (Cochran Q, P=0.63; I2=0%).
The researchers also looked at outcomes for patients with standard-risk multiple myeloma. Among those with standard-risk newly diagnosed disease, all three trials showed a significant improvement in PFS in the regimens containing daratumumab. In the meta-analysis, the addition of daratumumab also showed a PFS benefit for newly diagnosed disease (pooled HR 0.45, 95% CI 0.37-0.54, P<0.001). Similar benefit was seen within each of the three trials for patients with relapsed or refractory disease. Again, the meta-analysis showed a similar benefit (pooled HR 0.38, 95% CI 0.26-0.56, P<0.001).
Several limitations were noted by Giri and colleagues, including a lack of analysis of other subsets of high-risk disease, such as those with extramedullary disease or P53 mutations.
“The present analysis provided evidence that, when combined with backbone proteasome inhibitor and immunomodulatory agent-based regimens, daratumumab was associated with improved PFS among patients with high-risk multiple myeloma and standard-risk multiple myeloma in the context of newly diagnosed and relapsed or refractory disease,” the researchers wrote.
“However, it did not provide a comparison between daratumumab-based and non–daratumumab-based regimens,” they continued. “The identification of the best regimen and therapeutic strategy for patients with high-risk multiple myeloma may be achieved by network meta-analysis, preferentially using individual patient data and by future well-designed randomized clinical trials.”