Efficacy of Frontline Treatments for Newly Diagnosed Transplant-Ineligible Multiple Myeloma, a Network Meta-Analysis

Background: The introduction of novel agents, including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, has greatly expanded the treatment armamentarium of multiple myeloma (MM). However, there is no consensus on the optimal frontline treatment in patients with newly diagnosed transplant-ineligible MM, given lacking head-to-head comparisons of novel agents-containing multi-drug regimens in the context of rapidly evolving treatment modalities. To guide an evidence-based decision-making process, we performed a network meta-analysis (NMA) to compare the effectiveness of different frontline treatment regimens with novel agents in patients with newly diagnosed transplant-ineligible MM.

Methods: Relevant randomized controlled trials (RCTs) that enrolled patients with newly diagnosed transplant-ineligible MM who received novel-agent-based frontline treatments were identified by searching records in PubMed, Embase, Cochrane databases, and major haematology-oncology conferences published between 1998 and 2021. High-risk disease was defined by the presence of specific cytogenetic changes, including t(4;14), t(14;16), and/or del(17p). Patients without these cytogenetic changes were considered to have standard-risk disease. Records were screened and selected by two authors independently following the PRISMA guidelines, and the evidence was synthesized using a fixed-effect frequentist NMA. The outcome of interest in this study was progression-free survival (PFS), which was evaluated using hazard ratio (HR) and 95% confidence interval (CI) of HR. The preferred treatment options were identified using p-score. Risk of bias was assessed using the Cochrane RoB tool (version 2).

Results: We screened 9875 records and identified 9 RCTs with overall low-moderate risk of bias. They were linked into two separate networks based on the availability of a shared comparator. In network 1, three RCTs with four treatment regimens were included, and bortezomib-melphalan-prednisolone (VMP) was used as the common comparator. Quadruplet therapy of daratumumab-bortezomib-melphalan-prednisolone (D-VMP) was shown to be the most preferred option (HR 0.50, 95% CI 0.38-0.65, p < 0.001). Six trials with seven treatment regimens were used to synthesize network 2 using lenalidomide-dexamethasone (Rd) as the common comparator. Daratumumab-lenalidomide-dexamethasone (D-Rd) was identified to be the highest ranked treatment option (HR 0.53, 95% CI 0.43-0.66, p < 0.001). When limiting the analysis to RCTs with cytogenetic risk data, we showed that daratumumab-containing multi-drug regimens remained the preferred options across standard (network 1, D-VMP, HR 0.39, 95% CI 0.28-0.55, p < 0.001; network 2, D-Rd, HR 0.50, 95% CI 0.39-0.64, p < 0.001) and high-risk (D-Rd, HR 0.55, 95% CI 0.32-0.94, p = 0.03) patients.

Conclusion: Daratumumab-containing multi-drug regimens are the preferred treatment options in patients with newly diagnosed transplant-ineligible MM regardless of the cytogenetic risk.

Soekojo:Pfizer: Other: advisory board. Ooi:Abbvie: Honoraria; Pfizer: Honoraria; astellas: Honoraria; Novartis: Honoraria; Jenssen: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria. Chng:Hummingbird: Research Funding; Takeda: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; BMS: Honoraria; Celgene: Honoraria, Research Funding; J&J: Honoraria, Research Funding; Amgen: Honoraria.