Evaluation of Daratumumab for the Treatment of Multiple Myeloma in Patients With High-risk Cytogenetic Factors: A Systematic Review and Meta-analysis

Abstract

Importance: The addition of daratumumab to backbone multiple myeloma (MM) regimens is associated with improved response rates and progression-free survival (PFS). Whether improved outcomes are also associated with this regimen among patients with cytogenetically defined high-risk MM (HRMM) remains unclear.

Objective: To measure PFS associated with adding daratumumab to backbone MM regimens among patients with HRMM.

Data sources: For this systematic review and meta-analysis, MEDLINE, Embase, PubMed, Scopus, Web of Science Core Collection, Cochrane Library, clinical trials registries, and meeting libraries were searched from inception to January 2, 2020, using terms reflecting multiple myeloma and daratumumab.

Study selection: Included studies were phase 3 randomized clinical trials that compared backbone MM regimens with the same regimen plus daratumumab in newly diagnosed or relapsed or refractory MM, such that the only difference between the intervention and control groups was use of daratumumab and reported outcomes by cytogenetic risk. High-risk MM was defined as the presence of t(4;14), t(14;16), or del(17p).

Data extraction and synthesis: Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, 2 investigators independently extracted study data, with disagreements resolved by a third investigator. Quality was assessed by the Cochrane risk-of-bias method.

Main outcomes and measures: Data on effectiveness were extracted using hazard ratios (HRs) for PFS. Relative log-HRs were pooled using a DerSimonian-Laird random-effects model. Heterogeneity was assessed using the Cochran Q and the I2 statistic.

Results: Of 5194 studies screened, 6 phase 3 trials were eligible, including 3 trials for newly diagnosed MM (2528 patients; 358 with HRMM) and 3 trials for relapsed or refractory MM (1533 patients; 222 with HRMM). Among patients with newly diagnosed HRMM, the addition of daratumumab to backbone regimens was 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%). Similar results were seen among patients with relapsed or refractory HRMM (pooled HR, 0.45; 95% CI, 0.30-0.67; P < .001), again with little evidence of heterogeneity (Cochran Q, P = .63; I2 = 0%).

Conclusions and relevance: This study suggests that incorporating daratumumab to backbone regimens may be associated with improved PFS among patients with newly diagnosed HRMM or relapsed or refractory HRMM.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Giri reported receiving research funding from Carevive Systems and Pack Health LLC and honoraria from Carevive Systems. Dr Dimopoulos reported receiving honoraria from Janssen, Celgene, Takeda, Amgen, and Bristol Myers Squibb and serving as a consultant or in an advisory role for Janssen, Celgene, Takeda, Amgen, and Bristol Myers Squibb. Dr Facon reported receiving fees for serving on a board of directors, advisory committee, and speakers bureau from Celgene, Janssen, and Takeda and fees for serving on a board of directors and advisory committee from Amgen, Sanofi, Karyopharm, Oncopeptides, and Roche. Dr Usmani reported received research funding from Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda; consulting fees from Amgen, BMS, Celgene, GSK, Janssen, Merck, Sanofi, SkylineDx, and Takeda; and speaking fees from Amgen, Celgene, Janssen, and Takeda. Dr Mateos reported receiving honoraria from Amgen, Celgene, Janssen, and Takeda and serving as a consultant or in an advisory role for Amgen, GlaxoSmithKline, Celgene, Janssen, Takeda, and AbbVie. Dr Costa reported receiving research funding from Amgen and Janssen and honoraria from Karyopharm, Celgene, Amgen, Janssen, and Sanofi. No other disclosures were reported.

Figures

Figure 1.. PRISMA Flow Diagram

Figure 2.. Outcomes Associated With the Addition of Daratumumab to Backbone Multiple Myeloma Regimens for Patients With High-risk Multiple Myeloma

Significant improvement in progression-free survival was seen among patients with first-line and relapsed or refractory disease. Squares represent mean values, with the size of the squares representing the weight, and horizonal lines represent 95% CIs. Diamonds are pooled means with the points representing 95% CIs. IV indicates inverse variance.

Figure 3.. Outcomes Associated With the Addition of Daratumumab to Backbone Multiple Myeloma Regimens for Patients With Standard-Risk Multiple Myeloma

Significant improvement in progression-free survival was seen among patients with first-line and relapsed or refractory disease. Squares represent mean values, with the size of the squares representing the weight, and horizonal lines represent 95% CIs. Diamonds are pooled means with the points representing 95% CIs. IV indicates inverse variance.