Adding Daratumumab to Multiple Myeloma Backbone Regimens May Improve PFS

Incorporating daratumumab (Darzalex) into backbone regimens may be associated with improved progression-free survival (PFS) in patients with high-risk multiple myeloma and standard-risk multiple myeloma in the context of newly diagnosed and relapsed or refractory disease, according to a systemic review and meta-analysis published in JAMA Oncology.

Even further, a lack of substantial heterogeneity suggested that the benefit appears to be consistent regardless of the underlying backbone myeloma regimen.

“These findings are of direct clinical relevance and may help clinicians choose an optimal anti-myeloma regimen for patients with high-risk cytogenetic factors,” the authors wrote.

Researchers searched MEDLINE, Embase, PubMed, Scopus, Web of Science Core Collection, Cochrane Library, clinical trials registries, and meeting libraries using terms reflecting multiple myeloma and daratumumab. Studies included in the analysis were phase 3 randomized clinical trials that compared backbone multiple myeloma regimens with the same regimen plus daratumumab in newly diagnosed or relapsed or refractory multiple myeloma, where the only difference between the intervention and control groups was the use of daratumumab and reported outcomes by cytogenetic risk.

Two investigators independently extracted the study data using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, with any disputes resolved by a third investigator. Moreover, quality was assessed using the Cochrane risk-of-bias method.

The primary end point for the study was PFS, defined as the time from randomization to the date of first confirmed progression or date of death, whichever occurred first.

Of a total of 5194 studies screened, 6 phase 3 trials were deemed eligible, including 3 trials for newly diagnosed multiple myeloma consisting of 2528 patients (358 with high-risk multiple myeloma) and 3 trials for relapsed or refractory multiple myeloma consisting of 1533 patients (222 with high-risk multiple myeloma).

Among those with newly diagnosed high-risk multiple myeloma, the addition of daratumumab to backbone regimens was found to be associated with improved PFS (pooled HR, 0.67; 95% CI, 0.47-0.95; P = .02), with little evidence of heterogeneity (Cochran Q, P = .77; I2 = 0%). Similarly, among patients with relapsed or refractory high-risk multiple myeloma the addition of daratumumab to backbone regimens was associated with improved PFS (pooled HR, 0.45; 95% CI, 0.30-0.67; P < .001), again with little evidence of heterogeneity (Cochran Q, P = .63; I2 = 0%).

“The findings suggest that daratumumab is associated with improved PFS among patients with newly diagnosed [high-risk multiple myeloma] and [standard-risk multiple myeloma],” the authors wrote. “This finding was not weakened by the 3 trials entering the analysis having different backbone [multiple myeloma] regimens and different age groups, as supported by the lack of significant heterogeneity in effect size.”

Of note, this analysis did not address the benefit associated with daratumumab in other subsets of patients recognized as high risk, such as patients with extramedullary disease, high lactate dehydrogenase levels at diagnosis, stage 3 disease, and inferior performance status at enrollment. Additionally, it did not examine the association of daratumumab with PFS among patients with a specific high-risk cytogenetic abnormality, such as del(17p).

Moving forward, the investigators suggested that 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.”

Reference:

Giri A, Grimshaw A, Bal S, et al. Evaluation of Daratumumab for the Treatment of Multiple Myeloma in Patients With High-risk Cytogenetic Factors. JAMA Oncology. doi: 10.1001/jamaoncol.2020.4338